KR20230119013A - Novel LRRK2 inhibitors - Google Patents

Novel LRRK2 inhibitors Download PDF

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KR20230119013A
KR20230119013A KR1020237025042A KR20237025042A KR20230119013A KR 20230119013 A KR20230119013 A KR 20230119013A KR 1020237025042 A KR1020237025042 A KR 1020237025042A KR 20237025042 A KR20237025042 A KR 20237025042A KR 20230119013 A KR20230119013 A KR 20230119013A
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compound
amino
disease
halogen
alkyl
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강은지
신재홍
김현진
이재영
조대현
고은
김승찬
송상옥
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주식회사 스탠다임
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P25/16—Anti-Parkinson drugs
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

본 발명은 화학식 1의 신규한 류신-풍부 반복 키나제 2(leucine-rich repeat kinase 2: LRRK2) 억제제, 이를 포함하는 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환의 예방 또는 치료용 약학적 조성물, 및 이를 이용한 질병의 치료 및 예방 방법에 관한 것이다. 본 발명에 따른 화합물은 LRRK2 저해 활성이 우수하여 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환(예컨대, 파킨슨병)의 예방 또는 치료에 효과적으로 사용될 수 있다.The present invention relates to a novel leucine-rich repeat kinase 2 (LRRK2) inhibitor of Formula 1, a pharmaceutical composition for preventing or treating a disease or disorder mediated by or related to LRRK2 including the same, and a pharmaceutical composition comprising the same It relates to methods for treating and preventing diseases using the present invention. The compound according to the present invention has excellent LRRK2 inhibitory activity and can be effectively used for preventing or treating diseases or disorders (eg, Parkinson's disease) mediated by or related to LRRK2.

Description

신규한 LRRK2 억제제 Novel LRRK2 inhibitors

본 발명은 화학식 1의 류신-풍부 반복 키나제 2(leucine-rich repeat kinase 2: LRRK2) 억제제, 이를 포함하는 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환의 예방 또는 치료용 약학적 조성물, 및 이를 이용한 질병의 치료 및 예방 방법에 관한 것이다.The present invention relates to a leucine-rich repeat kinase 2 (LRRK2) inhibitor of Formula 1, a pharmaceutical composition for preventing or treating a disease or disorder mediated by or related to LRRK2 including the same, and a disease using the same It relates to treatment and prevention methods of

퇴행성 뇌질환, 예컨대 파킨슨병은 수백만명에게 발병되고 있다. 파킨슨병은 중뇌 도파민 뉴런의 진행성 결손에 의해 유발되어, 환자의 움직임을 지시하고 제어하는 능력이 손상된다.Degenerative brain diseases such as Parkinson's disease affect millions of people. Parkinson's disease is caused by progressive deficits in dopamine neurons in the midbrain, which impairs the patient's ability to direct and control movement.

류신-풍부 반복 키나제 2(leucine-rich repeat kinase 2: LRRK2)는 유전성 파킨슨병에 관련되어 있다. 예를 들어, LRRK2 Gly2019Ser 돌연변이는 키나제 활성의 증가를 야기하는 것으로서, 유전성 파킨슨병을 야기한다. 파킨슨병 외에도, 알츠하이머병, 운동이상증, 중추신경계 장애, 암, 류마티스 관절염, 강직성 척추염과 관련이 있는 것으로 보고되었다. 또한, 유전체 연관 분석을 통해 LRRK2가 크론병과도 관련이 있는 것으로 알려졌다(Teri A. Manolio, N Engl J Med 2010;363:166-176). LRRK2와 질병들간의 관련성이 알려지면서, LRRK2의 조절제 또는 억제제들이 개발되고 있다(예컨대, 공개특허 제2020-0085779호(2020.07.15)).Leucine-rich repeat kinase 2 (LRRK2) has been implicated in hereditary Parkinson's disease. For example, LRRK2 Gly2019Ser mutations lead to increased kinase activity, resulting in hereditary Parkinson's disease. In addition to Parkinson's disease, it has been reported to be associated with Alzheimer's disease, dyskinesia, central nervous system disorders, cancer, rheumatoid arthritis, and ankylosing spondylitis. In addition, LRRK2 is known to be associated with Crohn's disease through genome association analysis (Teri A. Manolio, N Engl J Med 2010;363:166-176). As the association between LRRK2 and diseases is known, modulators or inhibitors of LRRK2 are being developed (eg, Patent Publication No. 2020-0085779 (July 15, 2020)).

따라서, 본 발명의 목적은 LRRK2에 대해 우수한 저해 활성을 나타내는 화학식 1의 화합물을 제공하고, 이를 이용하여 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환, 예를 들어 퇴행성 신경질환의 치료 및 예방에 높은 효능을 달성하는 것이다.Accordingly, an object of the present invention is to provide a compound of Formula 1 exhibiting excellent inhibitory activity against LRRK2, and using the same, to treat and prevent diseases or disorders mediated by or related to LRRK2, such as neurodegenerative diseases, with high efficacy is to achieve

본 발명의 목적은 화학식 1의 화합물을 제공하는 것이다.An object of the present invention is to provide a compound of formula (1).

본 발명의 또다른 목적은 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환을 예방 또는 치료하기 위한 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease or condition mediated by or related to LRRK2.

본 발명의 또다른 목적은 LRRK2 억제제를 이용하여 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환을 예방 또는 치료 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating a disease or condition mediated by or related to LRRK2 using a LRRK2 inhibitor.

본 출원에서 개시된 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 출원에서 개시된 다양한 요소들의 모든 조합이 본 출원의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 출원의 범주가 제한된다고 볼 수 없다.Each description and embodiment disclosed in this application can also be applied to each other description and embodiment. That is, all combinations of various elements disclosed in this application fall within the scope of this application. In addition, the scope of the present application is not to be construed as being limited by the specific descriptions described below.

본 발명의 일 양상은 하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 제공한다:One aspect of the present invention provides a compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

Figure pct00001
Figure pct00001

상기 화학식 1에서, R1은 할로겐으로 치환된 C1-6 알킬일 수 있다. 또한, 상기 R1은 F, Cl, Br 및 I로 이루어진 군으로부터 각각 독립적으로 선택된 1~3개의 할로겐 원자로 치환된 C1-3 알킬일 수 있다. 예컨대, R1은 CF3, CHF2, CH2F, CH2CF3, CH2CHF2, CH2CH2F, CH2CH2CF3, CH2CH2CHF2, CH2CH2CH2F, CCl3, CHCl2, CH2Cl, CH2CCl3, CH2CHCl2, CH2CH2Cl, CH2CH2CCl3, CH2CH2CHCl2, CH2CH2CH2Cl, CBr3, CHBr2, CH2Br, CH2CBr3, CH2CHBr2, CH2CH2Br, CH2CH2CBr3, CH2CH2CHBr2, CH2CH2CH2Br, CI3, CHI2, CH2I, CH2CI3, CH2CHI2, CH2CH2I, CH2CH2CI3, CH2CH2CHI2, CH2CH2CH2I 등일 수 있다.In Formula 1, R 1 may be C 1-6 alkyl substituted with halogen. In addition, R 1 may be C 1-3 alkyl substituted with 1 to 3 halogen atoms each independently selected from the group consisting of F, Cl, Br and I. For example, R 1 is CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH 2 CH 2 CHF 2 , CH 2 CH 2 CH 2 F, CCl 3 , CHCl 2 , CH 2 Cl, CH 2 CCl 3 , CH 2 CHCl 2 , CH 2 CH 2 Cl, CH 2 CH 2 CCl 3 , CH 2 CH 2 CHCl 2 , CH 2 CH 2 CH 2 Cl , CBr 3 , CHBr 2 , CH 2 Br, CH 2 CBr 3 , CH 2 CHBr 2 , CH 2 CH 2 Br, CH 2 CH 2 CBr 3 , CH 2 CH 2 CHBr 2 , CH 2 CH 2 CH 2 Br, CI 3 , CHI 2 , CH 2 I, CH 2 CI 3 , CH 2 CHI 2 , CH 2 CH 2 I, CH 2 CH 2 CI 3 , CH 2 CH 2 CHI 2 , CH 2 CH 2 CH 2 I and the like.

상기 화학식 1에서, R2는 할로겐; OH; CN; 아미노; 니트로; C1-6 알킬; C1-6 알콕시; 포르밀; C1-6 알킬카보닐; 모노- 또는 디-C1-6 알킬아미노; 포르밀아미노; C1-6 알킬카보닐아미노; 모노- 또는 디-C1-6 알킬아미노카보닐; 포르밀옥시; 및 C1-6 알킬카보닐옥시로 이루어진 군으로부터 선택될 수 있다. R2에서 상기 C1-6 알킬, C1-6 알콕시, C1-6 알킬카보닐, 모노- 또는 디-C1-6 알킬아미노, C1-6 알킬카보닐아미노, 모노- 또는 디-C1-6 알킬아미노카보닐, 및 C1-6 알킬카보닐옥시는 할로겐, OH, CN, 아미노 또는 니트로로 임의로 치환될 수 있다. 이 때, n은 0 내지 3의 정수일 수 있다.In Formula 1, R 2 is halogen; OH; CN; amino; nitro; C 1-6 alkyl; C 1-6 alkoxy; formyl; C 1-6 alkylcarbonyl; mono- or di-C 1-6 alkylamino; formylamino; C 1-6 alkylcarbonylamino; mono- or di-C 1-6 alkylaminocarbonyl; formyloxy; and C 1-6 alkylcarbonyloxy. wherein R 2 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, mono- or di-C 1-6 alkylamino, C 1-6 alkylcarbonylamino, mono- or di- C 1-6 alkylaminocarbonyl, and C 1-6 alkylcarbonyloxy may be optionally substituted with halogen, OH, CN, amino or nitro. In this case, n may be an integer from 0 to 3.

또한, R2는 할로겐; OH; CN; 아미노; 니트로; C1-6 알킬; C1-6 알콕시; C1-6 알킬카보닐; 및 모노- 또는 디-C1-6 알킬아미노로 이루어진 군으로부터 선택되고, 상기 C1-6 알킬, C1-6 알콕시, C1-6 알킬카보닐, 및 모노- 또는 디-C1-6 알킬아미노는 할로겐, OH, CN, 아미노 또는 니트로로 임의로 치환될 수 있다. 이 경우, n은 0 내지 2의 정수일 수 있다. 일 실시태양에서, R2는 할로겐, CN, 할로겐으로 임의로 치환된 C1-6 알킬, 할로겐으로 임의로 치환된 C1-6 알콕시, 할로겐으로 임의로 치환된 C1-6 알킬카보닐, 또는 할로겐으로 임의로 치환된 모노- 또는 디-C1-6 알킬아미노일 수 있다. 이 때, n은 0 내지 2의 정수일 수 있다.In addition, R 2 is halogen; OH; CN; amino; nitro; C 1-6 alkyl; C 1-6 alkoxy; C 1-6 alkylcarbonyl; and mono- or di-C 1-6 alkylamino, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, and mono- or di-C 1-6 Alkylamino may be optionally substituted with halogen, OH, CN, amino or nitro. In this case, n may be an integer from 0 to 2. In one embodiment, R 2 is halogen, CN, C 1-6 alkyl optionally substituted with halogen, C 1-6 alkoxy optionally substituted with halogen, C 1-6 alkylcarbonyl optionally substituted with halogen, or halogen. optionally substituted mono- or di-C 1-6 alkylamino. In this case, n may be an integer from 0 to 2.

상기 화학식 1에서, 고리 A 및 B는 각각 독립적으로, 페닐 고리 또는 피리미딘 고리에 결합된 N과 함께, 임의로 N, O 및 S에서 선택된 1개의 추가 헤테로원자를 포함하는 3원 내지 10원 헤테로모노사이클릴일 수 있다.In Formula 1, rings A and B are each independently a 3- to 10-membered heteromono group, together with N bonded to a phenyl ring or pyrimidine ring, optionally including one additional heteroatom selected from N, O and S. may be cyclyl.

또한, 상기 고리 A 및 B는 각각 독립적으로, 페닐 고리 또는 피리미딘 고리에 결합된 N과 함께, 임의로 N, O 및 S에서 선택된 1개의 추가 헤테로 원자를 포함하는 4원 내지 9원 헤테로모노사이클릴일 수 있다. 일 실시태양에서, 고리 A 및 고리 B는 각각 독립적으로 페닐 고리 또는 피리미딘 고리에 결합된 N과 함께, 임의로 N, O 및 S에서 선택된 1개의 추가 헤테로 원자를 포함하는 4원 내지 7원 헤테로모노사이클릴일 수 있다.In addition, the rings A and B are each independently a 4- to 9-membered heteromonocyclyl group containing one additional heteroatom optionally selected from N, O and S, together with N bonded to a phenyl ring or a pyrimidine ring. can In one embodiment, ring A and ring B are each independently a 4- to 7-membered heteromono group comprising N attached to the phenyl ring or pyrimidine ring, optionally including 1 additional heteroatom selected from N, O and S. may be cyclyl.

또한, 상기 고리 A 및 B는 각각 독립적으로, 아제티딘일, 피롤리딘일, 피페리딘일, 피페라진일, 모르폴린일, 티오모르폴린일, 아제판일, 디아제판일 및 옥사제판일, 티아제판일로 이루어진 군으로부터 선택되는 것일 수 있다. 일 실시태양에서, 고리 A 및 B는 각각 독립적으로, 아제티딘일, 피롤리딘일, 피페리딘일, 모르폴린일, 아제판일 또는 옥사제판일일 수 있다. 일 실시태양에서, 고리 A 및 고리 B 중 적어도 하나는 각각 독립적으로 페닐 고리 또는 피리미딘 고리에 결합된 N과 함께, 임의로 N, O 및 S에서 선택된 1개의 추가 헤테로 원자를 포함하는 5원 또는 6원 헤테로모노사이클릴일 수 있다.In addition, the rings A and B are each independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl and oxazepanyl, thiazepan It may be selected from the group consisting of days. In one embodiment, rings A and B may each independently be azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl or oxazepanyl. In one embodiment, at least one of Ring A and Ring B is a 5-membered or 6-membered ring each independently comprising 1 additional heteroatom, optionally selected from N, O and S, together with N bonded to the phenyl ring or pyrimidine ring. It may be a heteromonocyclyl.

일 실시태양에서, 고리 A의 크기는 고리 B의 크기와 같거나 이보다 클 수 있다. 예를 들면, 고리 B가 4원 헤테로모노사이클릴일 경우, 고리 A는 4원 이상의 헤테로모노사이클릴일 수 있다. 또는, 고리 B가 5원 헤테로모노사이클릴일 경우, 고리 A는 5원 이상의 헤테로모노사이클릴일 수 있다. 일 실시태양에서, 고리 B는 4원 헤테로모노사이클릴이고, 고리 A는 4원, 5원, 6원 또는 7원 헤테로모노사이클릴일 수 있다. 일 실시태양에서, 고리 B는 5원 헤테로모노사이클릴이고, 고리 A는 5원, 6원 또는 7원 헤테로모노사이클릴일 수 있다. 일 실시태양에서, 고리 B는 6원 헤테로모노사이클릴이고, 고리 A는 6원 또는 7원 헤테로모노사이클릴일 수 있다. 일 실시태양에서, 고리 B는 아제티딘일이고, 고리 A는 아제티딘일, 피롤리딘일, 피페리딘일, 모르폴린일, 아제판일 또는 옥사제판일일 수 있다. 일 실시태양에서, 고리 B는 피롤리딘일이고, 고리 A는 피롤리딘일, 피페리딘일, 모르폴린일, 아제판일 또는 옥사제판일일 수 있다. 일 실시태양에서, 고리 B는 피페리딘일 또는 모르폴린일이고, 고리 A는 피페리딘일, 모르폴린일, 아제판일 또는 옥사제판일일 수 있다.In one embodiment, the size of ring A can be equal to or greater than the size of ring B. For example, when Ring B is a 4-membered heteromonocyclyl, Ring A may be a 4-membered or higher heteromonocyclyl. Alternatively, when ring B is a 5-membered heteromonocyclyl, ring A may be a 5-membered or more heteromonocyclyl. In one embodiment, ring B is a 4-membered heteromonocyclyl and ring A can be a 4-, 5-, 6- or 7-membered heteromonocyclyl. In one embodiment, ring B is a 5-membered heteromonocyclyl and ring A can be a 5-, 6-, or 7-membered heteromonocyclyl. In one embodiment, ring B is a 6-membered heteromonocyclyl and ring A can be a 6- or 7-membered heteromonocyclyl. In one embodiment, ring B is azetidinyl and ring A can be azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl or oxazepanyl. In one embodiment, ring B is pyrrolidinyl and ring A can be pyrrolidinyl, piperidinyl, morpholinyl, azepanyl or oxazepanyl. In one embodiment, ring B is piperidinyl or morpholinyl, and ring A can be piperidinyl, morpholinyl, azepanyl or oxazepanyl.

일 실시태양에서, 고리 B는 피롤리딘일일 수 있다. 이 경우, 상기 피롤리딘일은 2개 이상의 할로겐으로 치환될 수 있다. 예를 들면, 상기 피롤리딘일은 제1 할로겐 및 제2 할로겐으로 치환될 수 있다. 일 실시태양에서, 상기 제1 할로겐 및 제2 할로겐은 상기 피롤리딘일 고리의 3번 위치에 같은자리(geminal) 치환되거나, 4번 위치에 같은자리 치환될 수 있다. 또는, 상기 제1 할로겐 및 상기 제2 할로겐은 상기 피롤리딘일 고리의 3번 및 4번 위치에 이웃자리(vicinal) 치환될 수 있다. 이 경우, 상기 제1 할로겐 및 상기 제2 할로겐은 시스(cis) 또는 트랜스(trans) 위치 관계를 가질 수 있다. 바람직하게는, 상기 제1 할로겐 및 상기 제2 할로겐은 트랜스 위치 관계를 가질 수 있다.In one embodiment, ring B can be pyrrolidinyl. In this case, the pyrrolidinyl may be substituted with two or more halogens. For example, the pyrrolidinyl may be substituted with a first halogen and a second halogen. In one embodiment, the first halogen and the second halogen may be geminal substituted at the 3-position or geminal substituted at the 4-position of the pyrrolidinyl ring. Alternatively, the first halogen and the second halogen may be vicinal substituted at positions 3 and 4 of the pyrrolidinyl ring. In this case, the first halogen and the second halogen may have a cis (cis) or trans (trans) positional relationship. Preferably, the first halogen and the second halogen may have a trans positional relationship.

상기 화학식 1에서, 고리 A 및 B는 할로겐; OH; CN; 옥소; 아미노; 니트로; C1-6 알킬; C1-6 알콕시; 모노- 또는 디-C1-6 알킬아미노; 및 N, O 및 S로부터 선택된 1~3개의 헤테로원자를 함유하는 3원 내지 8원 헤테로모노사이클릴로 이루어진 군으로부터 선택된 1~3개의 치환기로 임의로 치환될 수 있다. 이 때, 상기 C1-6 알킬, C1-6 알콕시, 모노- 또는 디-C1-6 알킬아미노는 할로겐, OH, CN, 옥소, 아미노 또는 니트로로 임의로 치환될 수 있고, 상기 3원 내지 8원 헤테로모노사이클릴은 할로겐, OH, CN, 옥소, 아미노, 니트로, C1-6 알킬, C1-6 알콕시, 모노- 또는 디-C1-6 알킬아미노로 임의로 치환될 수 있다.In Formula 1, rings A and B are halogen; OH; CN; iodine; amino; nitro; C 1-6 alkyl; C 1-6 alkoxy; mono- or di-C 1-6 alkylamino; and a 3- to 8-membered heteromonocyclyl containing 1 to 3 heteroatoms selected from N, O and S. In this case, the C 1-6 alkyl, C 1-6 alkoxy, mono- or di-C 1-6 alkylamino may be optionally substituted with halogen, OH, CN, oxo, amino or nitro, and the 3-membered to The 8-membered heteromonocyclyl may be optionally substituted with halogen, OH, CN, oxo, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, mono- or di-C 1-6 alkylamino.

또한, 고리 A 및 B는 각각 독립적으로, 할로겐; OH; CN; 옥소; 아미노; C1-6 알킬; C1-6 알콕시; 피롤리딘일; 피페리딘일; 피페라진일; 모르폴린일; 및 티오모르폴린일로 이루어진 군으로부터 선택된 1~3개의 치환기로 임의로 치환될 수 있다. 일 실시태양에서, 고리 A 및 B는 각각 독립적으로, 할로겐; OH; CN; 옥소; 아미노; C1-6 알킬; 및 모르폴린일로 이루어진 군으로부터 선택된 1~2개의 치환기로 임의로 치환될 수 있다.In addition, rings A and B are each independently selected from halogen; OH; CN; iodine; amino; C 1-6 alkyl; C 1-6 alkoxy; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; And it may be optionally substituted with 1 to 3 substituents selected from the group consisting of thiomorpholinyl. In one embodiment, rings A and B are each independently halogen; OH; CN; iodine; amino; C 1-6 alkyl; And it may be optionally substituted with 1 to 2 substituents selected from the group consisting of morpholinyl.

일 실시태양에서, 고리 A 및 고리 B 중 적어도 하나는 할로겐; OH; 또는 옥소로 치환되거나, 고리 A 및 고리 B 중 적어도 하나는 각각 페닐 고리 또는 피리미딘 고리에 결합된 N과 함께, O를 더 포함하는 헤테로모노사이클릴일 수 있다. 일 실시태양에서, 고리 A 및 고리 B 중 적어도 하나는 OH 또는 옥소로 치환되거나, 고리 A 및 고리 B 중 적어도 하나는 각각 페닐 고리 또는 피리미딘 고리에 결합된 N과 함께, O를 더 포함하는 헤테로모노사이클릴일 수 있다.In one embodiment, at least one of Ring A and Ring B is selected from halogen; OH; Or substituted with oxo, at least one of ring A and ring B may be a heteromonocyclyl further containing O together with N bonded to a phenyl ring or a pyrimidine ring, respectively. In one embodiment, at least one of Ring A and Ring B is substituted with OH or oxo, or at least one of Ring A and Ring B is a hetero group further comprising O, together with N bonded to a phenyl ring or pyrimidine ring, respectively. may be monocyclyl.

일 실시태양에서, 고리 A 또는 고리 B가 피롤리딘일; 피페리딘일; 피페라진일; 모르폴린일; 및 티오모르폴린일로 이루어진 군으로부터 선택된 치환기로 치환될 경우, 상기 치환기의 질소 원자가 상기 고리 A 또는 상기 고리 B에 결합될 수 있다. 예를 들면, 상기 치환기는 1-피롤리딘일; 1-피페리딘일; 1-피페라진일; 4-모르폴린일; 또는 4-티오모르폴린일일 수 있다.In one embodiment, ring A or ring B is pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; And when substituted with a substituent selected from the group consisting of thiomorpholinyl, the nitrogen atom of the substituent may be bonded to the ring A or the ring B. For example, the substituent may be 1-pyrrolidinyl; 1-piperidinyl; 1-piperazinyl; 4-morpholinyl; or 4-thiomorpholinyl.

용어 "알킬"은 완전 포화된 분지형 또는 비분지형 (또는, 직쇄 또는 선형) 탄화수소를 말한다. 상기 알킬은 치환 또는 비치환된 알킬기일 수 있다. 상기 C1-6 알킬은 C1 내지 C5, C1 내지 C4, C1 내지 C3, 또는 C1 내지 C2인 알킬기일 수 있다. 상기 알킬의 비제한적인 예로는 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, sec-부틸, n-펜틸, 이소펜틸, 네오펜틸, iso-아밀, 또는 n-헥실일 수 있다.The term "alkyl" refers to a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon. The alkyl may be a substituted or unsubstituted alkyl group. The C 1-6 alkyl may be an alkyl group of C 1 to C 5 , C 1 to C 4 , C 1 to C 3 , or C 1 to C 2 . Non-limiting examples of the alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, or n-hexyl. there is.

용어 "할로겐" 원자는 주기율표의 17족에 속하는 원자를 말한다. 할로겐 원자는 불소, 염소, 브롬, 및 요오드 등을 포함한다.The term "halogen" atom refers to an atom belonging to group 17 of the periodic table. Halogen atoms include fluorine, chlorine, bromine, iodine, and the like.

용어 "히드록시(hydroxy)"는 -OH 기능기(수산기)를 말한다.The term "hydroxy" refers to the -OH functional group (hydroxyl group).

용어 "알콕시(alkoxy)"는 산소 원자에 결합된 알킬을 말한다. 상기 C1 내지 C6의 알콕시기는 예를 들면, C1 내지 C5, C1 내지 C4, C1 내지 C3, 또는 C1 내지 C2인 알콕시기일 수 있다. 상기 알콕시기는 메톡시, 에톡시, 또는 프로폭시일 수 있다.The term "alkoxy" refers to an alkyl bonded to an oxygen atom. The C 1 to C 6 alkoxy group may be, for example, a C 1 to C 5 , C 1 to C 4 , C 1 to C 3 , or C 1 to C 2 alkoxy group. The alkoxy group may be methoxy, ethoxy, or propoxy.

용어 "아미노(amino)"기는 -NH2를 말한다.The term "amino" group refers to -NH 2 .

용어 "니트로(nitro)"는 -NO2를 말한다.The term "nitro" refers to -NO 2 .

용어 "시아노(cyano)"는 -CN으로서, 탄소 원자와 질소 원자 사이에 삼중결합으로 이루어진 작용기를 말한다.The term "cyano" is -CN, and refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.

용어 "옥소(oxo)"는 =O를 지칭하며, "옥소로 치환된"은 탄소 원자가 -C(=O)-의 형태로 =O 치환기를 갖는 것을 의미한다.The term "oxo" refers to =O, and "substituted with oxo" means that the carbon atom has a =O substituent in the form of -C(=O)-.

용어 "알킬아미노"는 아미노(-NH2)기의 1개 또는 2개의 수소 원자가 상기 언급된 알킬기 중 어느 하나 또는 둘로 치환된 작용기를 의미하며, 모노-알킬아미노기와 디-알킬아미노기를 모두 포함하고, 디-알킬아미노기에서 2개의 알킬기는 동일하거나 상이할 수 있다. 구체적으로, 모노-C1-6 알킬아미노는 아미노(-NH2)기의 1개의 수소 원자가 C1-6 알킬로 치환되고, 디-C1-6 알킬아미노는 아미노(-NH2)기의 2개의 수소 원자가 동일하거나 상이한 C1-6 알킬로 치환될 수 있다. 예컨대, 모노-C1-6 알킬아미노기는 메틸아미노, 에틸아미노, 프로필아미노, 이소프로필아미노, 부틸아미노, 이소부틸아미노, 2급-부틸아미노, 3급-부틸아미노, 펜틸아미노, 헥실아미노 등을 포함할 수 있다. 디-C1-6 알킬아미노기는 예컨대, 디메틸아미노, 디에틸아미노, 디프로필아미노, 메틸에틸아미노, 메틸프로필아미노, 메틸이소프로필아미노, 메틸부틸아미노, 메틸이소부틸아미노, 에틸프로필아미노, 에틸이소프로필아미노, 에틸이소부틸아미노, 이소프로필이소부틸아미노, 메틸헥실아미노, 에틸헥실아미노 등을 포함할 수 있다.The term "alkylamino" refers to a functional group in which one or two hydrogen atoms of an amino (-NH 2 ) group are substituted with either or both of the above-mentioned alkyl groups, and includes both mono-alkylamino and di-alkylamino groups, , the two alkyl groups in a di-alkylamino group can be the same or different. Specifically, mono-C 1-6 alkylamino is an amino (-NH 2 ) group in which one hydrogen atom is substituted with C 1-6 alkyl, and di-C 1-6 alkylamino is an amino (-NH 2 ) group Two hydrogen atoms may be substituted with the same or different C 1-6 alkyl. For example, the mono-C 1-6 alkylamino group is methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino, and the like. can include The di-C 1-6 alkylamino group is, for example, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, methylisopropylamino, methylbutylamino, methylisobutylamino, ethylpropylamino, ethyliso propylamino, ethylisobutylamino, isopropylisobutylamino, methylhexylamino, ethylhexylamino and the like.

용어 "알킬카보닐"은 카보닐(CO)기를 통하여 분자의 나머지 부분에 연결된 알킬기를 의미하며, 여기서 "알킬"은 상기 정의된 의미를 갖는다. 예컨대, C1-6 알킬카보닐은 아세틸, 프로피오닐, 부티릴, 이소부티릴, 발레릴, 이소발레릴, 피발로일, 헥사노일, 헵타노일 등을 포함한다.The term "alkylcarbonyl" refers to an alkyl group linked to the remainder of the molecule through a carbonyl (CO) group, wherein "alkyl" has the meaning defined above. For example, C 1-6 alkylcarbonyl includes acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, and the like.

용어 "알킬카보닐아미노"는 알킬-C(O)-NH-기를 의미하며, 아세틸아미노, 프로피오닐아미노, 부티릴아미노, 이소부티릴아미노, 발레릴아미노, 이소발레릴아미노, 피발로일아미노, 헥사노일아미노, 헵타노일아미노 등을 포함한다.The term "alkylcarbonylamino" refers to the group alkyl-C(O)-NH- and includes acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino , hexanoylamino, heptanoylamino and the like.

용어 "알킬아미노카보닐"은 알킬-NHC(O)-기를 의미하며, 예컨대, C1-6 알킬아미노카보닐은 아세트아미도, 프로필아미노카보닐, 부틸아미노카보닐, 이소부틸아미노카보닐, 펜틸아미노카보닐, 헥실아미노카보닐 등을 포함한다.The term “alkylaminocarbonyl” refers to an alkyl-NHC(O)-group, eg C 1-6 alkylaminocarbonyl is acetamido, propylaminocarbonyl, butylaminocarbonyl, isobutylaminocarbonyl, pentylaminocarbonyl, hexylaminocarbonyl, and the like.

용어 "알킬카보닐옥시"는 알킬-C(O)-O-기를 의미하며, 예컨대, C1-6 알킬카보닐옥시는 아세톡시, 프로피오닐옥시, 부티릴옥시, 이소부티릴옥시, 발레릴옥시, 이소발레릴옥시, 피발로일옥시, 헥사노일옥시, 헵타노일옥시 등을 포함한다.The term "alkylcarbonyloxy" refers to an alkyl-C(O)-O- group, eg C 1-6 alkylcarbonyloxy is acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryl oxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, heptanoyloxy, and the like.

용어 "포르밀"은 HC(O)-기를 의미하고, 용어 "포르밀옥시"는 HC(O)-O-기를 의미하며, 용어 "포르밀아미노"는 HC(O)-NH-기를 의미한다.The term "formyl" refers to the group HC(O)-, the term "formyloxy" refers to the group HC(O)-O-, and the term "formylamino" refers to the group HC(O)-NH- .

용어 "헤테로모노사이클릴"은 적어도 하나의 헤테로원자를 포함하는 포화 또는 부분 불포화의 모노사이클릭(monocyclic) 탄화수소기를 말한다. 헤테로모노사이클릴기는 3 내지 20개, 3 내지 10개, 3개 내지 8개, 3개 내지 7개, 3개 내지 6개, 4개 내지 9개, 4개 내지 8개, 4개 내지 7개, 4개 내지 6개의 고리 원자를 함유할 수 있다. 상기 헤테로원자는 N, O 및 S로 이루어진 군으로부터 선택된 어느 하나 이상일 수 있다. 상기 헤테로원자는 N, O, 및 S로 이루어진 군으로부터 선택된 1개 내지 3개의 헤테로원자일 수 있다. 또한, 상기 헤테로원자는 N 및 O로부터 선택된 1개 또는 2개의 헤테로원자일 수 있다.The term "heteromonocyclyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon group containing at least one heteroatom. 3 to 20, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 4 to 9, 4 to 8, 4 to 7 heteromonocyclyl groups , and may contain 4 to 6 ring atoms. The heteroatom may be at least one selected from the group consisting of N, O and S. The heteroatom may be 1 to 3 heteroatoms selected from the group consisting of N, O, and S. In addition, the heteroatom may be one or two heteroatoms selected from N and O.

헤테로모노사이클릴의 비제한적인 예로는 아지리딘일, 아제티딘일, 피롤리딘일, 피페리딘일, 피페라진일, 모르폴린일, 티오모르폴린일, 아제판일, 디아제판일, 옥사제판일, 티아제판일 등을 들 수 있다.Non-limiting examples of heteromonocyclyl include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thia A plate making date etc. are mentioned.

상기 "치환 또는 비치환된"의 용어 "치환"은 유기 화합물 중의 하나 이상의 수소 원자를 다른 원자단으로 치환하여 유도체를 형성한 경우 수소 원자 대신에 도입되는 것을 말하고, "치환기"는 도입된 원자단을 말한다. 치환기는 예를 들면, 할로겐, OH, CN, 옥소, 아미노, 니트로, C1-6 알킬, C1-6 알콕시, 모노- 또는 디-(C1-6 알킬)아미노, 또는 N, O 및 S로부터 선택된 1~3개의 헤테로원자를 함유하는 3원 내지 8원 헤테로모노사이클릴일 수 있고, 상기 치환기는 할로겐, OH, CN, 옥소, 아미노, 니트로, C1-6 알킬, C1-6 알콕시, 모노- 또는 디-(C1-6 알킬)아미노로 추가로 치환될 수 있다.The term "substituted" in the above "substituted or unsubstituted" refers to what is introduced in place of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and "substituent" refers to an introduced atomic group. . Substituents are, for example, halogen, OH, CN, oxo, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, mono- or di-(C 1-6 alkyl)amino, or N, O and S It may be a 3- to 8-membered heteromonocyclyl containing 1 to 3 heteroatoms selected from, wherein the substituents are halogen, OH, CN, oxo, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, mono- or di-(C 1-6 alkyl)amino.

상기 화학식 1의 화합물은 하기 반응식 A에 따라서 제조할 수 있다.The compound of Formula 1 can be prepared according to Reaction Scheme A below.

[반응식 A][Scheme A]

Figure pct00002
Figure pct00002

상기 단계 1에서 고리 A를 포함하는 아민 화합물 및 R2로 치환된 4-플루오로-니트로벤젠 화합물을 적절한 유기 용매, 예컨대, N,N-디이소프로필에틸아민(DIPEA 또는 DIEA로 약칭함), 아세토니트릴(ACN), 디클로로메탄(DCM) 중에서 반응시킬 수 있다. 일 실시태양에서 상기 반응은 약 10℃ 내지 약 120℃, 약 20℃ 내지 약 100℃, 또는 약 50℃ 내지 약 80℃에서 약 수 시간 내지 밤새(overnight), 약 12시간 내지 약 18시간, 약 16시간 동안 수행할 수 있다.In step 1, the amine compound containing ring A and the 4-fluoro-nitrobenzene compound substituted with R 2 are mixed with an appropriate organic solvent such as N,N-diisopropylethylamine (abbreviated as DIPEA or DIEA), It can be reacted in acetonitrile (ACN) or dichloromethane (DCM). In one embodiment, the reaction is performed at about 10 ° C to about 120 ° C, about 20 ° C to about 100 ° C, or about 50 ° C to about 80 ° C for about several hours to overnight, about 12 hours to about 18 hours, about It can be done in 16 hours.

상기 단계 2에서, 단계 1에서 수득된 생성물의 -NO2기를 적절한 환원 반응 조건, 예컨대, Pd/C 촉매 존재하의 수소 대기중에서 NH2기로 환원시킬 수 있다. 일 실시태양에서 상기 환원 반응은 EtOH와 같은 알콜 용매 중에서 약 10℃ 내지 약 50℃, 약 20℃ 내지 약 40℃ 또는 실온에서, 약 수십분 내지 수시간, 약 30분 내지 약 5시간, 약 1시간 내지 약 4시간 동안 수행할 수 있다.In step 2, the -NO 2 group of the product obtained in step 1 may be reduced to an NH 2 group under appropriate reduction reaction conditions, for example, in a hydrogen atmosphere in the presence of a Pd/C catalyst. In one embodiment, the reduction reaction is performed in an alcohol solvent such as EtOH at about 10 ° C to about 50 ° C, about 20 ° C to about 40 ° C or room temperature, about tens of minutes to several hours, about 30 minutes to about 5 hours, about 1 hour to about 4 hours.

상기 단계 3에서, 단계 2에서 수득된 아닐린 화합물 및 디클로로피리미딘 화합물을 적절한 유기 용매, 예컨대 디클로로에탄(DCE), t-부탄올(tBuOH) 등에서 임의로 적절한 촉매, 예컨대 ZnCl2, 트리에틸암모늄(TEA) 등의 존재 하에 혼합하여 반응시킬 수 있다. 일 실시태양에서, 상기 반응은 약 -10℃ 내지 약 25℃, 약 -5℃ 내지 약 10℃ 또는 약 0℃에서 약 1~5시간, 또는 약 2~3시간 동안 수행할 수 있다.In the above step 3, the aniline compound and the dichloropyrimidine compound obtained in step 2 are optionally mixed with a suitable catalyst such as ZnCl 2 , triethylammonium (TEA) in a suitable organic solvent such as dichloroethane (DCE), t-butanol (tBuOH), and the like. It can be mixed and reacted in the presence of the like. In one embodiment, the reaction may be performed at about -10°C to about 25°C, about -5°C to about 10°C, or about 0°C for about 1 to 5 hours, or about 2 to 3 hours.

상기 단계 4에서, 단계 3에서 수득한 화합물을 고리 B를 함유하는 아민 화합물과 적절한 유기 용매, 예컨대 DIPEA, ACN 중에서 약 10℃ 내지 약 80℃, 약 20℃ 내지 약 60℃ 또는 실온에서, 1시간 내지 밤새 동안 또는 2시간 내지 18시간 동안 반응시킬 수 있다.In step 4 above, the compound obtained in step 3 is mixed with an amine compound containing ring B in a suitable organic solvent such as DIPEA, ACN at about 10 ° C to about 80 ° C, about 20 ° C to about 60 ° C or room temperature for 1 hour. to overnight or for 2 to 18 hours.

고리 A 및 B, R1 및 R2에 따라서, 화학식 1의 화합물은 하기 반응식 A-1과 나타낸 바와 같이, 디클로로피리미딘 화합물과 고리 B를 포함하는 아민 화합물을 별도로 반응시켜서 수득한 생성물을 상기 단계 2의 생성물과 반응시켜서 제조할 수 있다.Depending on rings A and B, R 1 and R 2 , the compound of Formula 1 is a product obtained by separately reacting a dichloropyrimidine compound and an amine compound containing ring B, as shown in Scheme A-1 below, in the above step It can be prepared by reacting with the product of 2.

[반응식 A-1][Scheme A-1]

Figure pct00003
Figure pct00003

상기 반응식 A-1에서, 단계 3-1 및 단계 4-1은 반응식 A의 단계 3 및 4를 적절히 변형하여 수행될 수 있다. 예컨대, 단계 3-1은 적절한 용매, 예컨대 DIPEA, DMF, DCM, NMP(N-메틸피롤리돈) 중에서 필요에 따라서 K2CO3 등의 적절한 시약을 첨가하여 약 -80℃ 내지 약 50℃, 약 -70℃ 내지 약 30℃ 또는 약 실온에서 수십 분 내지 밤새 동안, 약 20분 내지 약 18시간 또는 약 30분 내지 약 12시간 반응을 수행할 수 있다.In Scheme A-1, Steps 3-1 and 4-1 may be performed by appropriately modifying Steps 3 and 4 of Scheme A. For example, in step 3-1, an appropriate reagent such as K 2 CO 3 is added in an appropriate solvent such as DIPEA, DMF, DCM, or NMP (N-methylpyrrolidone) as needed, and the temperature is about -80°C to about 50°C, The reaction can be carried out at about -70°C to about 30°C or about room temperature for several tens of minutes to overnight, about 20 minutes to about 18 hours, or about 30 minutes to about 12 hours.

또한, 단계 4-1은 DIPEA, n-BuOH 등의 적절한 용매 중에서 필요에 따라서 농염산과 같은 적절한 시약을 첨가하여, 약 실온 내지 약 150℃, 약 50℃ 내지 약 100℃, 또는 약 80℃ 내지 약 100℃에서, 수십 분 내지 수십 시간, 약 30분 내지 약 18시간, 또는 약 1시간 내지 약 12시간 동안 반응을 수행할 수 있다.In addition, step 4-1 is about room temperature to about 150 ° C, about 50 ° C to about 100 ° C, or about 80 ° C to about 80 ° C to about 150 ° C. At 100° C., the reaction can be carried out for tens of minutes to tens of hours, about 30 minutes to about 18 hours, or about 1 hour to about 12 hours.

상기 기술된 화학식 1의 화합물의 제조방법은 예시적인 것으로서, 최종 화합물을 수득하기 위한 출발 물질의 종류에 따라서 적절한 용매, 촉매, 반응 조건 등을 선택하여 변형할 수 있으며, 이러한 용매, 촉매, 반응 조건 등은 당업자의 기술자에게 널리 알려져 있다.The method for preparing the compound of Formula 1 described above is exemplary, and may be modified by selecting an appropriate solvent, catalyst, reaction conditions, etc. according to the type of starting material to obtain the final compound, and these solvents, catalysts, reaction conditions and the like are well known to those skilled in the art.

상기 화학식 1의 화합물은 하기 화합물로 이루어진 군으로부터 선택될 수 있다:The compound of Formula 1 may be selected from the group consisting of the following compounds:

Figure pct00004
Figure pct00005
Figure pct00006
Figure pct00004
Figure pct00005
Figure pct00006

Figure pct00007
Figure pct00008
Figure pct00009
Figure pct00007
Figure pct00008
Figure pct00009

Figure pct00010
Figure pct00011
Figure pct00012
Figure pct00010
Figure pct00011
Figure pct00012

Figure pct00013
Figure pct00014
Figure pct00015
Figure pct00013
Figure pct00014
Figure pct00015

Figure pct00016
Figure pct00017
Figure pct00018
Figure pct00016
Figure pct00017
Figure pct00018

Figure pct00019
Figure pct00020
Figure pct00021
Figure pct00019
Figure pct00020
Figure pct00021

Figure pct00022
Figure pct00023
Figure pct00024
Figure pct00022
Figure pct00023
Figure pct00024

Figure pct00025
Figure pct00026
Figure pct00027
Figure pct00025
Figure pct00026
Figure pct00027

Figure pct00028
Figure pct00029
Figure pct00030
Figure pct00028
Figure pct00029
Figure pct00030

Figure pct00031
Figure pct00032
Figure pct00033
Figure pct00031
Figure pct00032
Figure pct00033

Figure pct00034
Figure pct00035
Figure pct00036
Figure pct00034
Figure pct00035
Figure pct00036

Figure pct00037
Figure pct00038
Figure pct00039
Figure pct00037
Figure pct00038
Figure pct00039

Figure pct00040
Figure pct00041
Figure pct00042
Figure pct00040
Figure pct00041
Figure pct00042

Figure pct00043
Figure pct00044
Figure pct00045
Figure pct00043
Figure pct00044
Figure pct00045

Figure pct00046
Figure pct00047
Figure pct00048
Figure pct00046
Figure pct00047
Figure pct00048

Figure pct00049
Figure pct00050
Figure pct00051
Figure pct00049
Figure pct00050
Figure pct00051

Figure pct00052
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Figure pct00054

Figure pct00055
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Figure pct00058
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Figure pct00060
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Figure pct00058
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Figure pct00060
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용어 "입체이성질체"의 "이성질체(isomer)"는 분자식은 같지만 분자 내에 있는 구성 원자의 연결 방식이나 공간 배열이 동일하지 않은 화합물을 말한다. 이성질체는 예를 들면, 구조 이성질체(structural isomers), 및 입체이성질체(stereoisomer)를 포함한다. 상기 입체이성질체는 부분입체 이성질체(diastereomer) 또는 거울상 이성질체(enantiomer)일 수 있다. 거울상이성질체는 왼손과 오른손의 관계처럼 그 거울상과 겹쳐지지 않는 이성질체를 말하고, 광학 이성질체(optical isomer)라고도 한다. 거울상 이성질체는 키랄 중심 탄소에 4개 이상의 치환기가 서로 다른 경우 R(Rectus: 시계방향) 및 S(Sinister: 반시계 방향)로 구분한다. 부분입체이성질체는 거울상 관계가 아닌 입체 이성질체를 말하고, 원자의 공간 배열이 달라 생기는 이성질체이다. 상기 부분입체이성질체는 시스(cis)-트랜스(trans) 이성질체 및 형태이성질체(conformational isomer 또는 conformer) 로 나뉠 수 있다."Isomer" of the term "stereoisomer" refers to a compound having the same molecular formula but not the same connection method or spatial arrangement of constituent atoms in a molecule. Isomers include, for example, structural isomers, and stereoisomers. The stereoisomers may be diastereomers or enantiomers. Enantiomers refer to isomers that do not overlap with their mirror images, such as the relationship between left and right hands, and are also called optical isomers. Enantiomers are classified as R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents differ from each other on the chiral central carbon. Diastereomers are stereoisomers that are not mirror images, and are isomers that result from differences in the arrangement of atoms in space. The diastereomers may be divided into cis-trans isomers and conformational isomers or conformers.

용어 "용매화물(solvate)"은 유기 또는 무기 용매에 용매화된 화합물을 말한다. 상기 용매화물은 예를 들어 수화물이다.The term "solvate" refers to a compound solvated in an organic or inorganic solvent. The solvate is, for example, a hydrate.

용어 "염(salt)"은 화합물의 무기 및 유기산 부가염을 말한다. 상기 약학적으로 허용가능한 염은 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 염일 수 있다. 상기 무기산염은 염산염, 브롬산염, 인산염, 황산염, 또는 이황산염일 수 있다. 상기 유기산염은 포름산염, 아세트산염, 프로피온산염, 젖산염, 옥살산염, 주석산염, 말산염, 말레인산염, 구연산염, 푸마르산염, 베실산염, 캠실산염, 에디실염, 트리클로로아세트산, 트리플루오로아세트산염, 벤조산염, 글루콘산염, 메탄술폰산염, 글리콜산염, 숙신산염, 4-톨루엔술폰산염, 갈룩투론산염, 엠본산염, 글루탐산염, 에탄술폰산염, 벤젠술폰산염, p-톨루엔술폰산염, 또는 아스파르트산염일 수 있다. 상기 금속염은 칼슘염, 나트륨염, 마그네슘염, 스트론튬염, 또는 칼륨염일 수 있다.The term "salt" refers to inorganic and organic acid addition salts of a compound. The pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The inorganic acid salt may be a hydrochloride, bromate, phosphate, sulfate, or bisulfate salt. The organic acid salt is formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edisyl salt, trichloroacetic acid, trifluoroacetate , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate may be an acid salt. The metal salt may be a calcium salt, sodium salt, magnesium salt, strontium salt, or potassium salt.

상기 화학식 1의 화합물은 LRRK2(Leucine-rich repeat kinase 2) 저해제일 수 있다. 상기 LRRK2는 류신-풍부 반복 키나제 패밀리(leucine-rich repeat kinase family)에 속하는 단백질일 수 있다. 상기 LRRK2는 AURA17, DARDARIN, PARK8, RIPK7, 또는 ROCO2로도 불릴 수 있다. 상기 LRRK2는 Uniprot No. Q5S007의 아미노산 서열을 포함하는 단백질일 수 있다. 상기 LRRK2는 Gly2019Ser 돌연변이를 포함할 수 있다.The compound of Formula 1 may be a Leucine-rich repeat kinase 2 (LRRK2) inhibitor. The LRRK2 may be a protein belonging to the leucine-rich repeat kinase family. The LRRK2 may also be called AURA17, DARDARIN, PARK8, RIPK7, or ROCO2. The LRRK2 is Uniprot No. It may be a protein comprising the amino acid sequence of Q5S007. The LRRK2 may include a Gly2019Ser mutation.

본 발명의 다른 양상은 일 양상에 따른 화학식 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 포함하는, LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환을 예방 또는 치료하기 위한 약학적 조성물을 제공한다.Another aspect of the present invention is a pharmaceutical agent for preventing or treating a disease or disorder mediated by or related to LRRK2, including a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to one aspect. It provides an enemy composition.

상기 화학식 1의 화합물, 입체이성질체, 용매화물, 약학적으로 허용가능한 염, 및 LRRK2는 전술한 바와 같다.The compounds of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, and LRRK2 are as described above.

LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환은 퇴행성 신경질환일 수 있다. 용어 "퇴행성 신경질환(neurodegenerative disease)"은 신경계의 퇴행성 변화와 관련된 모든 질환을 지칭하며, 구체적으로 뇌의 퇴행성 변화와 관련된 퇴행성 뇌질환을 지칭할 수 있다. 상기 퇴행성 뇌질환은 파킨슨병(Parkinson's disease), 알츠하이머병(Alzheimer's disease), 헌팅턴병(Huntington's disease), 경도인지장애(mild cognitive impairment), 아밀로이드증(amyloidosis), 다계통위측증(Multiple system atrophy), 다발성경화증(multiple sclerosis), 타우병증(tauopathies), 픽병(Pick's disease), 노인성 치매, 근위축성 측삭 경화증(amyotrophic lateral sclerosis), 척수소뇌성 운동실조증(Spinocerebellar Atrophy), 뚜렛 증후군(Tourette's Syndrome), 프리드리히 보행실조(Friedrich's Ataxia), 마차도-조셉 병(Machado-Joseph's disease), 루이 소체 치매(Lewy Body Dementia), 근육긴장이상(Dystonia), 진행성 핵상 마비(Progressive Supranuclear Palsy) 및 전두측두엽 치매(Frontotemporal Dementia)로 이루어진 군에서 선택될 수 있다.A disease or condition mediated by or associated with LRRK2 may be a neurodegenerative disease. The term "neurodegenerative disease" refers to any disease associated with degenerative changes in the nervous system, and may specifically refer to degenerative brain diseases associated with degenerative changes in the brain. The degenerative brain diseases include Parkinson's disease, Alzheimer's disease, Huntington's disease, mild cognitive impairment, amyloidosis, multiple system atrophy, multiple Multiple sclerosis, tauopathies, Pick's disease, senile dementia, amyotrophic lateral sclerosis, Spinocerebellar Atrophy, Tourette's Syndrome, Friedrich Gait Friedrich's Ataxia, Machado-Joseph's disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy and Frontotemporal Dementia can be selected from the group consisting of

LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환은 운동이상증, 중추신경계 장애, 암, 류마티스 관절염, 강직성 척추염, 크론병, 염증성 장질환(Inflammatory Bowel Disease) 및 결핵으로 이루어진 군으로부터 선택되는 질환일 수 있다.The disease or condition mediated by or related to LRRK2 may be a disease selected from the group consisting of dyskinesia, central nervous system disorders, cancer, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, inflammatory bowel disease and tuberculosis.

상기 약학적 조성물은 퇴행성 뇌질환 예방, 치료, 또는 개선 활성을 갖는 공지의 유효 성분을 더 포함할 수 있다. 퇴행성 뇌질환 예방, 치료, 또는 개선 활성을 갖는 공지의 유효 성분은 예컨대 카르비도파(carbidopa)와 같은 탈탄산효소(decarboxylase) 저해제, 레보도파(levodopa), 카테콜-O-메틸트랜스퍼라제(Catechol-O-methyltransferase: COMT) 저해제, 도파민 작용제, MAO-B(monoamine oxidase B) 저해제, 아만타딘, 항콜린제, 아세틸콜린에스터라제(acetylcholinesterase) 저해제 또는 NMDA 수용체 길항제(N-Methyl-D-aspartate receptor antagonist)일 수 있다. COMT 저해제는 오피카폰(opicapone), 엔타카폰(entacapone) 및 톨카폰(tolcapone)일 수 있다. 도파민 작용제는 브로모크립틴(bromocriptine), 페르골리드(pergolide), 프라미펙솔(pramipexole), 로피니롤(ropinirole), 피리베딜(piribedil), 카베르골린(cabergoline), 아포모르핀(apomorphine) 및 리수리드(lisuride)일 수 있다. MAO-B 저해제는 사핀아미드(safinamide), 세레길린(selegiline), 및 라사길린(rasagiline)이다. 아세틸콜린에스터라제 저해제는 타크린(tacrine), 리바스티그민(rivastigmine), 갈란타민(galantamine) 및 도네페질(donepezil)일 수 있다. NMDA 수용체 길항제는 메만틴(memantine)일 수 있다. 상기 화학식 1로 표시되는 화합물, 이의 유도체, 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염과 상기 공지의 유효 성분은 동시 또는 순차 투여를 위한 단일 또는 개별 조성물일 수 있다.The pharmaceutical composition may further include a known active ingredient having an activity to prevent, treat, or improve degenerative brain disease. Known active ingredients having preventive, therapeutic, or ameliorative activities of degenerative brain diseases include, for example, decarboxylase inhibitors such as carbidopa, levodopa, and catechol-O-methyltransferase (Catechol-O-methyltransferase). O-methyltransferase (COMT) inhibitors, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, amantadine, anticholinergics, acetylcholinesterase inhibitors, or N-Methyl-D-aspartate receptor antagonists can be COMT inhibitors may be opicapone, entacapone and tolcapone. Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, and apomorphine. and lisuride. MAO-B inhibitors are safinamide, selegiline, and rasagiline. Acetylcholinesterase inhibitors may be tacrine, rivastigmine, galantamine and donepezil. The NMDA receptor antagonist may be memantine. The compound represented by Formula 1, its derivative, stereoisomer, solvate, or pharmaceutically acceptable salt and the known active ingredient may be a single or separate composition for simultaneous or sequential administration.

용어 "예방"은 상기 약학적 조성물의 투여에 의해 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환의 발생을 억제하거나 그의 발병을 지연시키는 모든 행위를 말한다. 용어 "치료"는 상기 약학적 조성물의 투여에 의해 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환의 증세가 호전되거나 이롭게 변경하는 모든 행위를 말한다.The term "prevention" refers to all actions that suppress or delay the onset of a disease or disorder mediated by or related to LRRK2 by administration of the pharmaceutical composition. The term "treatment" refers to any activity that improves or beneficially alters the symptoms of a disease or disorder mediated by or related to LRRK2 by administration of the pharmaceutical composition.

상기 약학적 조성물은 약학적으로 허용가능한 담체를 포함할 수 있다. 상기 담체는 부형제, 희석제 또는 보조제를 포함하는 의미로 사용된다. 상기 담체는 예를 들면, 락토스, 덱스트로스, 수크로스, 소르비톨, 만니톨, 자일리톨, 에리트리톨, 말티톨, 전분, 아카시아 고무, 알기네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 폴리비닐 피롤리돈, 물, 생리식염수, PBS와 같은 완충액, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트, 및 미네랄 오일로 이루어진 군으로부터 선택된 것일 수 있다. 상기 조성물은 충진제, 항응집제, 윤활제, 습윤제, 풍미제, 유화제, 보존제, 또는 이들의 조합을 포함할 수 있다.The pharmaceutical composition may include a pharmaceutically acceptable carrier. The carrier is used as a meaning including an excipient, diluent or auxiliary agent. Such carriers include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl fibre, It may be selected from the group consisting of Rolidone, water, physiological saline, a buffer such as PBS, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil. The composition may include fillers, anti-agglomerating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, or combinations thereof.

상기 약학적 조성물은 통상의 방법에 따라 임의의 제형으로 준비될 수 있다. 상기 조성물은 예를 들면, 경구 투여 제형(예를 들면, 분말, 정제, 캡슐, 시럽, 알약, 또는 과립), 또는 비경구 제형(예를 들면, 주사제)으로 제형화될 수 있다. 또한, 상기 조성물은 전신 제형, 또는 국부 제형으로 제조될 수 있다.The pharmaceutical composition may be prepared in any dosage form according to conventional methods. The composition may be formulated as, for example, an oral dosage form (eg, powder, tablet, capsule, syrup, pill, or granule), or a parenteral dosage form (eg, injection). In addition, the composition may be prepared as a systemic formulation or topical formulation.

상기 약학적 조성물에 있어서, 경구 투여를 위한 고형 제제는 정제, 환제, 산제, 과립제, 또는 캡슐제일 수 있다. 상기 고형 제제는 부형제를 더 포함할 수 있다. 부형제는 예를 들면, 전분, 칼슘 카보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose), 또는 젤라틴일 수 있다. 또한, 상기 고형 제제는 마그네슘 스테아레이트, 또는 탈크와 같은 윤활제를 더 포함할 수 있다. 상기 약학적 조성물에 있어서, 경구를 위한 액상 제제는 현탁제, 내용액제, 유제, 또는 시럽제일 수 있다. 상기 액상 제제는 물, 또는 리퀴드 파라핀을 포함할 수 있다. 상기 액상 제제는 부형제, 예를 들면 습윤제, 감미제, 방향제, 또는 보존제를 포함할 수 있다. 상기 약학적 조성물에 있어서, 비경구 투여를 위한 제제는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 또는 및 좌제일 수 있다. 비수성용제 또는 현탁제는 식물성 기름 또는 에스테르를 포함할 수 있다. 식물성 기름은 예를 들면, 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 또는 올리브 오일일 수 있다. 에스테르는 예를 들면 에틸올레이트일 수 있다. 좌제의 기제는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 또는 글리세로젤라틴일 수 있다.In the pharmaceutical composition, the solid preparation for oral administration may be tablets, pills, powders, granules, or capsules. The solid formulation may further include an excipient. The excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, the solid preparation may further include a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, the oral liquid formulation may be a suspension, internal solution, emulsion, or syrup. The liquid formulation may include water or liquid paraffin. The liquid formulation may contain excipients such as wetting agents, sweetening agents, flavoring agents, or preservatives. In the pharmaceutical composition, preparations for parenteral administration may be sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried or suppositories. Non-aqueous solvents or suspensions may include vegetable oils or esters. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The base of the suppository may be witepsol, macrogol, tween 61, cacao butter, laurin fat, or glycerogelatin.

상기 약학적 조성물은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 상기 약학적 조성물의 유효 성분으로 포함한다. "유효 성분"은 약리학적 활성(예를 들면, 퇴행성 뇌질환 치료)을 달성하기 위해 사용되는 생리활성 물질을 말한다.The pharmaceutical composition includes the compound according to one aspect, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof as an active ingredient of the pharmaceutical composition. "Active ingredient" refers to a physiologically active substance used to achieve pharmacological activity (eg, treatment of degenerative brain disease).

상기 약학적 조성물은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 유효한 양으로 포함할 수 있다. 용어 "유효한 양"은 예방 또는 치료를 필요로 하는 개체에게 투여되는 경우 질병의 예방 또는 치료의 효과를 나타내기에 충분한 양을 말한다. 상기 유효한 양은 당업자가 선택되는 세포 또는 개체에 따라 적절하게 선택할 수 있다. 상기 약학적 조성물의 바람직한 투여량은 개체의 상태 및 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 상기 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염은 예를 들면, 약 0.0001 ㎎/㎏ 내지 약 100 ㎎/㎏, 또는 약 0.001 ㎎/㎏ 내지 약 100 ㎎/㎏의 양을 1일 1회 내지 24회, 2일 내지 1주에 1 내지 7회, 또는 1개월 내지 12개월에 1 내지 24회로 나누어 투여할 수 있다. 상기 약학적 조성물에서 상기 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염은 전체 조성물 총 중량에 대하여 약 0.0001 중량% 내지 약 10 중량%, 또는 약 0.001 중량% 내지 약 1 중량%로 포함될 수 있다.The pharmaceutical composition may contain an effective amount of a compound according to one aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof. The term "effective amount" refers to an amount sufficient to exhibit the effect of preventing or treating a disease when administered to a subject in need of such prevention or treatment. The effective amount can be appropriately selected by those skilled in the art depending on the cell or organism to be selected. A preferred dosage of the pharmaceutical composition varies depending on the condition and body weight of the subject, the severity of the disease, the type of drug, the route and period of administration, but can be appropriately selected by those skilled in the art. However, the compound, its stereoisomer, solvate, or pharmaceutically acceptable salt can be used in an amount of, for example, about 0.0001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 100 mg/kg. It may be divided into 1 to 24 times per day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times per 1 month to 12 months. In the pharmaceutical composition, the compound, its stereoisomer, solvate, or pharmaceutically acceptable salt is from about 0.0001% to about 10% by weight, or from about 0.001% to about 1% by weight, based on the total weight of the composition. can be included

투여 방법은 경구, 또는 비경구 투여일 수 있다. 투여 방법은 예를 들어, 경구, 경피, 피하, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 국소, 코안(intranasal), 기관내(intratracheal), 또는 피내 경로일 수 있다. 상기 조성물은 전신적으로 또는 국부적으로 투여될 수 있고, 단독으로 또는 다른 약학적 활성 화합물과 함께 투여될 수 있다.The administration method may be oral or parenteral administration. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes. The composition may be administered systemically or topically, and may be administered alone or in combination with other pharmaceutically active compounds.

본 발명의 다른 양상은 일 양상에 따른 화학식 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 개체에게 투여하는 단계를 포함하는 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환을 예방 또는 치료하는 방법을 제공한다.Another aspect of the present invention is to prevent a disease or disorder mediated by or related to LRRK2, comprising administering to a subject a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to one aspect. Or provide a method of treatment.

상기 화학식 1의 화합물, 입체이성질체, 용매화물, 약학적으로 허용가능한 염, LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환, 예방, 및 치료는 전술한 바와 같다.The compounds of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, diseases or disorders mediated by or related to LRRK2, prevention, and treatment are as described above.

상기 개체는 포유동물, 예를 들면, 인간, 마우스, 래트, 소, 말, 돼지, 개, 원숭이, 양, 염소, 유인원, 또는 고양이일 수 있다. 상기 개체는 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환과 연관된 증상을 앓고 있거나, 앓을 가능성이 큰 개체일 수 있다.The subject may be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat, ape, or cat. The subject may be an individual suffering from, or likely to suffer from, a disease mediated by or related to LRRK2 or symptoms associated with a disease.

상기 방법은 상기 개체에 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환을 예방 또는 치료하는 효과의 공지의 유효 성분을 투여하는 단계를 더 포함할 수 있다. 상기 공지의 유효 성분은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염과 동시, 개별, 또는 순차로 상기 개체에 투여될 수 있다.The method may further include administering to the subject a known active ingredient having an effect of preventing or treating a disease or condition mediated by or related to LRRK2. The known active ingredient may be administered to the subject simultaneously, separately, or sequentially with the compound according to one aspect, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

투여 방법은 경구, 또는 비경구 투여일 수 있다. 투여 방법은 예를 들어, 경구, 경피, 피하, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 국소, 코안(intranasal), 기관내(intratracheal), 또는 피내 경로일 수 있다. 상기 약학적 조성물은 전신적으로 또는 국부적으로 투여될 수 있고, 단독으로 또는 다른 약학적 활성 화합물과 함께 투여될 수 있다.The administration method may be oral or parenteral administration. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes. The pharmaceutical composition may be administered systemically or topically, and may be administered alone or in combination with other pharmaceutically active compounds.

상기 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 상기 투여량은 예를 들어, 성인 기준으로 약 0.001 ㎎/kg 내지 약 100 ㎎/kg, 약 0.01 ㎎/kg 내지 약 10 ㎎/kg, 또는 약 0.1 ㎎/kg 내지 약 1 ㎎/kg의 범위 내 일 수 있다. 상기 투여는 1일 1회, 1일 다회, 또는 1주일에 1회, 2주일에 1회, 3주일에 1회, 또는 4주일에 1회 내지 1년에 1회 투여될 수 있다.A preferred dosage of the pharmaceutical composition varies depending on the condition and body weight of the patient, the severity of the disease, the type of drug, the route and period of administration, but can be appropriately selected by those skilled in the art. The dosage is, for example, in the range of about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 10 mg/kg, or about 0.1 mg/kg to about 1 mg/kg on an adult basis. can be The administration may be administered once a day, multiple times a day, or once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks to once a year.

본 발명의 다른 양상은 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환을 예방 또는 치료에 사용하기 위한, 일 양상에 따른 화학식 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도를 제공한다.Another aspect of the present invention is the use of the compound of Formula 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof according to one aspect for use in preventing or treating a disease or condition mediated by or related to LRRK2. to provide.

본 발명의 다른 양상은 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환을 예방 또는 치료하기 위한 의약을 제조하기 위한, 일 양상에 따른 화학식 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도를 제공한다.Another aspect of the present invention is a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable compound according to one aspect for preparing a medicament for preventing or treating a disease or disorder mediated by or related to LRRK2. Use of the salt is provided.

상기 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환, 예방, 치료, 화학식 1의 화합물, 입체이성질체, 용매화물, 및 약학적으로 허용가능한 염은 전술한 바와 같다.The diseases or conditions mediated by or related to LRRK2, prevention, treatment, compounds of formula 1, stereoisomers, solvates, and pharmaceutically acceptable salts are as described above.

본 발명에 따른 화학식 1의 화합물은 LRRK2 저해 활성이 우수하여 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환(예컨대, 파킨슨병)의 예방 또는 치료용 약학적 조성물, 및 이를 이용한 질병의 치료 및 예방 방법에 효과적으로 사용될 수 있다.The compound represented by Chemical Formula 1 according to the present invention has excellent LRRK2 inhibitory activity, and thus is suitable for pharmaceutical compositions for preventing or treating diseases or disorders (eg, Parkinson's disease) mediated by or related to LRRK2, and methods for treating and preventing diseases using the same. can be used effectively.

이하 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.It will be described in more detail through the following examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

제조예 1: 2-클로로-4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘Preparation Example 1: 2-chloro-4- (3,3-difluoropyrrolidin-1-yl) -5- (trifluoromethyl) pyrimidine

Figure pct00061
Figure pct00061

DMF (10 mL) 중의 2,4-디클로-5-(트리플루오로메틸)피리미딘 (600 mg， 26.5 mmol，1.2당량) 용액에 3,3-디플루오로피롤리딘 염산염 (330.83 mg, 2.30 mmol, 1당량) 및 DIEA (595.64 mg, 4.61 mmol, 802.75 uL, 2당량)를 첨가하고, 혼합물을 20℃에서 12시간 동안 교반하였다. TLC (석유에테르 : 에틸아세테이트 = 10:1, 원하는 생성물 Rf = 0.4)는 반응이 완료되었음을 나타내었다. LCMS (t=1.323)는 원하는 생성물을 나타내었다. 이후 혼합물을 감압 농축시키고, 잔사를 얼음물 (15 mL)에 부어 10분 동안 교반하였다. 수성상을 에틸아세테이트 (15 mL×3)로 추출하였다. 유기상을 모아서 염수 (30 mL)로 세척하고, 무수 Na2SO4로 건조시켜서 여과하고 진공 하에 농축시켰다. 잔사를 실리카겔 컬럼 크로마토그래피 (석유에테르/에틸아세테이트 = 20/1, 10/1)로 정제하여 2-클로로-4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘 (210 mg, 31.7% 수율)을 백색 고체로 수득하였다. 1H-NMR (CDCl3, 400 MHz) δ (ppm): 8.47 (s, 1 H), 4.08-3.91 (m, 4 H), 2.57-2.39 (m, 2 H); LCMS: RT = 1.323분, MS m/z: 288.4 [M+H]+.3,3-difluoropyrrolidine hydrochloride (330.83 mg, 2.30 mmol, 1 equiv.) and DIEA (595.64 mg, 4.61 mmol, 802.75 uL, 2 equiv.) were added and the mixture was stirred at 20° C. for 12 h. TLC (petroleum ether : ethyl acetate = 10:1, desired product Rf = 0.4) showed the reaction to be complete. LCMS (t=1.323) showed the desired product. Then, the mixture was concentrated under reduced pressure, and the residue was poured into ice water (15 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (15 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, 10/1) to obtain 2-chloro-4-(3,3-difluoropyrrolidin-1-yl)-5-( Obtained trifluoromethyl)pyrimidine (210 mg, 31.7% yield) as a white solid. 1 H-NMR (CDCl 3 , 400 MHz) δ (ppm): 8.47 (s, 1 H), 4.08-3.91 (m, 4 H), 2.57-2.39 (m, 2 H); LCMS: RT = 1.323 min, MS m/z: 288.4 [M+H] + .

제조예 2: (3S,4R)-1-(4-아미노페닐)-4-메틸피롤리딘-3-올Preparation Example 2: (3S,4R)-1-(4-aminophenyl)-4-methylpyrrolidin-3-ol

Figure pct00062
Figure pct00062

단계 1: (3S,4R)-3-히드록시-4-메틸피롤리딘 트리플루오로아세테이트의 합성Step 1: Synthesis of (3S,4R)-3-hydroxy-4-methylpyrrolidine trifluoroacetate

DCM (5 mL) 중에 tert-부틸 (3S,4R)-3-히드록시-4-메틸피롤리딘-1-카르복실레이트 (500 mg, 2.48 mmol, 1당량) 용액을 혼합하고, 트리플루오로아세트산(TFA) (5.39g, 47.27 mmol, 3.5 mL, 19.03당량)을 0℃에서 첨가하였다. 혼합물을 20℃에서 5시간 동안 교반하였다. TLC (염화메틸렌 : 메탄올 = 10:1, 원하는 생성물 Rf = 0.13)는 반응이 완료되었음을 보여주었다. 혼합물을 감압 농축시켜서 (3S,4R)-3-히드록시-4-메틸피롤리딘 트리플루오로아세테이트 (230 mg, 미정제, TFA)를 갈색 오일로 수득하였다. 1H-NMR (CDCl3, 400 MHz) δ (ppm): 9.48 (br s, 1 H), 4.04-4.16 (m, 1 H), 3.92 (br s, 1 H), 3.20-3.34 (m, 2 H), 2.92 (br s, 1 H), 2.69-2.83 (m, 1 H), 2.21-2.39 (m, 1 H), 0.84-1.02 (m, 3 H).A solution of tert-butyl (3S,4R)-3-hydroxy-4-methylpyrrolidine-1-carboxylate (500 mg, 2.48 mmol, 1 equiv) in DCM (5 mL) was mixed and trifluoro Acetic acid (TFA) (5.39 g, 47.27 mmol, 3.5 mL, 19.03 equiv) was added at 0 °C. The mixture was stirred at 20 °C for 5 hours. TLC (methylene chloride : methanol = 10:1, desired product Rf = 0.13) showed the reaction to be complete. The mixture was concentrated under reduced pressure to give (3S,4R)-3-hydroxy-4-methylpyrrolidine trifluoroacetate (230 mg, crude, TFA) as a brown oil. 1 H-NMR (CDCl 3 , 400 MHz) δ (ppm): 9.48 (br s, 1 H), 4.04-4.16 (m, 1 H), 3.92 (br s, 1 H), 3.20-3.34 (m, 2 H), 2.92 (br s, 1 H), 2.69–2.83 (m, 1 H), 2.21–2.39 (m, 1 H), 0.84–1.02 (m, 3 H).

단계 2: (3S,4R)-4-메틸-1-(4-니트로페닐)피롤리딘-3-올의 합성Step 2: Synthesis of (3S,4R)-4-methyl-1-(4-nitrophenyl)pyrrolidin-3-ol

상기 단계 1에서 수득된 화합물 (230 mg, 1.07 mmol, 1당량, TFA) 및 1-플루오로-4-니트로벤젠 (150.82 mg, 1.07 mmol, 113.40 uL, 1당량)의 N-메틸-2-피롤리돈(NMP)(2 mL) 용액에 K2CO3 (147.74 mg, 1.07 mmol, 1당량)을 첨가하고, 20℃에서 12시간 동안 교반하였다. TLC (석유에테르 : 에틸아세테이트 = 3:1, Rf = 0.4)는 반응이 완료되었음을 나타내었다. LCMS (t=1.420)는 원하는 생성물을 나타내었다. 잔사를 얼음물 (w/w = 1/1) (30 mL)에 부었다. 생성된 침전물을 여과하고 여과된 케이크를 수집하고 건조시켜서 (3S,4R)-4-메틸-1-(4-니트로페닐)피롤리딘-3-올 (185 mg, 77.9% 수율)를 황색 고체로 수득하였다. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.37-7.59 (m, 2 H), 6.60-6.73 (m, 2 H), 4.39 (d, J = 4.4 Hz, 1 H) 3.12 (q, J = 4.8 Hz, 2 H), 2.18-2.38 (m, 3 H), 1.78-1.90 (m, 1 H), 0.18 (s, 3 H); LCMS: RT = 1.420분, MS m/z: 223.5 [M+H]+.N-methyl-2-p of the compound obtained in step 1 above (230 mg, 1.07 mmol, 1 equiv., TFA) and 1 - fluoro-4-nitrobenzene (150.82 mg, 1.07 mmol, 113.40 uL, 1 equiv.) To a solution of Rolidone (NMP) (2 mL) was added K 2 CO 3 (147.74 mg, 1.07 mmol, 1 eq.) and stirred at 20° C. for 12 h. TLC (petroleum ether : ethyl acetate = 3:1, Rf = 0.4) showed the reaction to be complete. LCMS (t=1.420) showed the desired product. The residue was poured into ice water (w/w = 1/1) (30 mL). The resulting precipitate was filtered and the filtered cake was collected and dried to give (3S,4R)-4-methyl-1-(4-nitrophenyl)pyrrolidin-3-ol (185 mg, 77.9% yield) as a yellow solid. was obtained with 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 7.37-7.59 (m, 2 H), 6.60-6.73 (m, 2 H), 4.39 (d, J = 4.4 Hz, 1 H) 3.12 (q, J = 4.8 Hz, 2 H), 2.18–2.38 (m, 3 H), 1.78–1.90 (m, 1 H), 0.18 (s, 3 H); LCMS: RT = 1.420 min, MS m/z: 223.5 [M+H] + .

단계 3: (3S,4R)-1-(4-아미노페닐)-4-메틸피롤리딘-3-올의 합성Step 3: Synthesis of (3S,4R)-1-(4-aminophenyl)-4-methylpyrrolidin-3-ol

상기 단계 2에서 수득된 화합물(265 mg, 1.19 mmol, 1당량)의 EtOH (2 mL) 용액에 Pd/C (26.5 mg, 25.00 umol, 10% 순도)를 첨가하였다. 현탁액을 진공 하에 탈기하고 H2로 여러 번 퍼지(purge)하였다. 혼합물을 H2 (15 psi) 하에 25℃에서 2시간 동안 교반하였다. TLC (석유에테르:에틸아세테이트 = 3:1, Rf = 0.2)는 출발물질이 완전히 소모되었음을 나타내었다. 반응 혼합물을 여과하고, 여액을 농축시켜서 (3S,4R)-1-(4-아미노페닐)-4-메틸피롤리딘-3-올 (210 mg, 91.60% 수율)을 갈색 고체로 수득하였다. 추가 정제없이 다음 단계에 사용하였다. 1H-NMR (CDCl3, 400 MHz) δ (ppm): 6.82-6.92 (m, 1 H), 6.57-6.72 (m, 2 H), 6.38-6.56 (m, 1 H), 4.41 (br s, 2 H), 3.46-3.71 (m, 2 H), 2.40 (t, J = 8.0 Hz, 3 H), 2.17-2.34 (m, 1 H), 1.86-2.10 (m, 3 H), 1.11 (d, J = 7.2 Hz, 3 H); LCMS: RT = 0.360분, MS m/z: 193.1 [M+H]+.Pd/C (26.5 mg, 25.00 umol, 10% purity) was added to a solution of the compound obtained in step 2 (265 mg, 1.19 mmol, 1 equivalent) in EtOH (2 mL). The suspension was degassed under vacuum and purged several times with H 2 . The mixture was stirred at 25° C. under H 2 (15 psi) for 2 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.2) indicated that the starting material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated to give (3S,4R)-1-(4-aminophenyl)-4-methylpyrrolidin-3-ol (210 mg, 91.60% yield) as a brown solid. It was used in the next step without further purification. 1 H-NMR (CDCl 3 , 400 MHz) δ (ppm): 6.82-6.92 (m, 1 H), 6.57-6.72 (m, 2 H), 6.38-6.56 (m, 1 H), 4.41 (br s , 2 H), 3.46–3.71 (m, 2 H), 2.40 (t, J = 8.0 Hz, 3 H), 2.17–2.34 (m, 1 H), 1.86–2.10 (m, 3 H), 1.11 ( d, J = 7.2 Hz, 3 H); LCMS: RT = 0.360 min, MS m/z: 193.1 [M+H] + .

제조예 3: 2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘Preparation Example 3: 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidine

Figure pct00063
Figure pct00063

DCM (15 mL) 중에 2,4-디클로로-5-(트리플루오로메틸)피리미딘 (1.0g, 4.60 mmol, 1.00당량) 및 DIEA (1.7g, 13.82 mmol, 3.00당량)을 교반 혼합하고, DCM (5 mL) 중의 (3S,4S)-3,4-디플루오로피롤리딘 염산염 (661 mg, 4.60 mmol, 1.00당량)을 -70℃에서 적가하였다. 생성된 혼합물을 -70℃에서 30분 동안 교반하고, 감압 농축시켰다. 잔사를 PE/EtOAc (2:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘 (800 mg, 54%)을 백색 고체로 수득하였다. 1H-NMR (CDCl3, 400 MHz) δ (ppm): 8.50 (s, 1H), 5.38-5.35 (m, 1H), 5.26-5.23 (m, 1H), 4.19-4.07 (m, 2H), 4.00-3.94 (m, 1H), 3.90-3.84 (m, 1H); MS m/z: 288/290 [M+H]+.Stir-mix 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 g, 4.60 mmol, 1.00 equiv) and DIEA (1.7 g, 13.82 mmol, 3.00 equiv) in DCM (15 mL) and DCM (3S,4S)-3,4-difluoropyrrolidine hydrochloride (661 mg, 4.60 mmol, 1.00 equiv) in (5 mL) was added dropwise at -70°C. The resulting mixture was stirred at -70 °C for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5 Obtained -(trifluoromethyl)pyrimidine (800 mg, 54%) as a white solid. 1 H-NMR (CDCl 3 , 400 MHz) δ (ppm): 8.50 (s, 1H), 5.38-5.35 (m, 1H), 5.26-5.23 (m, 1H), 4.19-4.07 (m, 2H), 4.00-3.94 (m, 1H), 3.90-3.84 (m, 1H); MS m/z: 288/290 [M+H] + .

제조예 4: 4-[3-(벤질옥시)피페리딘-1-일]아닐린Preparation Example 4: 4-[3-(benzyloxy)piperidin-1-yl]aniline

Figure pct00064
Figure pct00064

단계 1: 1-(4-니트로페닐)피페리딘-3-올의 합성Step 1: Synthesis of 1-(4-nitrophenyl)piperidin-3-ol

ACN (10 mL) 중에 피페리딘-3-올 (1.00g, 9.88 mmol, 1.00당량) 및 4-플루오로니트로벤젠 (2.79g, 19.77 mmol, 2.00당량)을 교반 혼합하고, DIEA (3.83g, 29.63 mmol, 3.00당량)를 첨가하였다. 생성된 혼합물을 질소 대기하에 85℃에서 16시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 생성된 혼합물을 진공 하에 농축시키고, 잔사를 PE/EtOAc (1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 1-(4-니트로페닐)피페리딘-3-올 (1g, 43.24%)을 황색 고체로 수득하였다. MS m/z: 223 [M+H]+.Stir-mix piperidin-3-ol (1.00 g, 9.88 mmol, 1.00 equiv) and 4-fluoronitrobenzene (2.79 g, 19.77 mmol, 2.00 equiv) in ACN (10 mL), DIEA (3.83 g, 29.63 mmol, 3.00 equiv) was added. The resulting mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere, and the mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give 1-(4-nitrophenyl)piperidin-3-ol (1 g, 43.24%) was obtained as a yellow solid. MS m/z: 223 [M+H] + .

단계 2: 3-(벤질옥시)-1-(4-니트로페닐)피페리딘의 합성Step 2: Synthesis of 3-(benzyloxy)-1-(4-nitrophenyl)piperidine

DMF (10 mL) 중에 1-(4-니트로페닐)피페리딘-3-올 (1.00g, 4.50 mmol, 1.00당량)을 교반 혼합하고, 질소 대기하에 0℃에서 NaH (216 mg, 9.00 mmol, 2.00당량)를 나누어 첨가하였다. 생성된 혼합물을 질소 대기하에 0℃에서 30분 동안 교반하고, 상기 혼합물에 염화벤질 (1.14g, 9.00 mmol, 2.00당량)을 첨가하였다. 생성된 혼합물을 25℃에서 2시간 동안 더 교반하고, 반응을 물/얼음 (50 mL)로 ??칭시켰다. 생성된 혼합물을 EtOEt (2×50 mL)로 추출하고, 유기층을 모아서 염수 (2×50 mL)로 세척하여, 무수 Na2SO4 상에서 건조시켰다. 여과 후 여액을 감압 농축시키고, 잔사를 PE/EtOAc (1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 3-(벤질옥시)-1-(4-니트로페닐)피페리딘 (1g, 67.59%)를 황색 고체로 수득하였다. MS m/z: 313 [M+H]+.Stir-mix 1-(4-nitrophenyl)piperidin-3-ol (1.00 g, 4.50 mmol, 1.00 equiv) in DMF (10 mL) and add NaH (216 mg, 9.00 mmol, 2.00 equivalent) was added in portions. The resulting mixture was stirred at 0° C. for 30 min under a nitrogen atmosphere, and benzyl chloride (1.14 g, 9.00 mmol, 2.00 equiv) was added to the mixture. The resulting mixture was further stirred at 25 °C for 2 h and the reaction was quenched with water/ice (50 mL). The resulting mixture was extracted with EtOEt (2×50 mL) and the combined organic layers were washed with brine (2×50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain 3-(benzyloxy)-1-(4-nitrophenyl)piperidine (1 g, 67.59 %) was obtained as a yellow solid. MS m/z: 313 [M+H] + .

단계 3: 4-[3-(벤질옥시)피페리딘-1-일]아닐린의 합성Step 3: Synthesis of 4-[3-(benzyloxy)piperidin-1-yl]aniline

MeOH (10 mL) 중에 3-(벤질옥시)-1-(4-니트로페닐)피페리딘 (1.00g, 3.20 mmol, 1.00당량)을 교반 혼합하고, Pd/C (10%, 300 mg)를 첨가하였다. 수소 풍선을 사용하여 혼합물을 수소 대기하에 실온에서 1시간 동안 수소화하고, 셀라이트 패드를 통해 여과하고 감압 농축시켰다. 잔사를 PE/EtOAc (1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 4-[3-(벤질옥시)피페리딘-1-일]아닐린 (700 mg, 73.56%)을 연황색 고체로 수득하였다. MS m/z: 283 [M+H]+.Stir-mix 3-(benzyloxy)-1-(4-nitrophenyl)piperidine (1.00 g, 3.20 mmol, 1.00 equiv) in MeOH (10 mL), and Pd/C (10%, 300 mg) added. The mixture was hydrogenated for 1 hour at room temperature under a hydrogen atmosphere using a hydrogen balloon, filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to yield 4-[3-(benzyloxy)piperidin-1-yl]aniline (700 mg, 73.56%) as a pale yellow solid. obtained. MS m/z: 283 [M+H] + .

제조예 5: 2,4-디클로로-5-(3,3,3-트리플루오로프로필)피리미딘Preparation Example 5: 2,4-dichloro-5- (3,3,3-trifluoropropyl) pyrimidine

Figure pct00065
Figure pct00065

단계 1: 2,4-디메톡시-5-[(1E)-3,3,3-트리플루오로프로프-1-엔-1-일]피리미딘의 합성Step 1: Synthesis of 2,4-dimethoxy-5-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]pyrimidine

THF (10 mL) 및 H2O (2 mL) 중에 2,4-디메톡시피리미딘-5-일보론산 (1.00g, 5.43 mmol, 1.00당량) 및 (1E)-1-클로로-3,3,3-트리플루오로프로프-1-엔 (1.42g, 10.88 mmol, 2.00당량)을 혼합하고, Pd2(dba)3 (1.00g, 1.08 mmol, 0.20당량) 및 [(t-Bu)3PH]BF4 (630 mg, 2.17 mmol, 0.4당량)를 첨가하였다. 생성된 혼합물을 질소 대기하에 60℃에서 8시간 동안 교반하고 혼합물을 실온으로 냉각하여 물 (50 mL)로 희석시키고 EtOAc (3×100 mL)로 추출하였다. 유기층을 모아서 무수 황산나트륨 상에서 건조하고 감압 농축시켰다. 조 생성물을 PE/EtOAc (1:2)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2,4-디메톡시-5-[(1E)-3,3,3-트리플루오로프로프-1-엔-1-일]피리미딘 (890 mg, 66%)을 연황색 고체로 수득하였다. MS m/z: 235 [M+H]+.2,4-Dimethoxypyrimidin-5-ylboronic acid (1.00 g, 5.43 mmol, 1.00 equiv) and (1E)-1-chloro-3,3 in THF (10 mL) and H 2 O (2 mL). ,3-Trifluoroprop-1-ene (1.42 g, 10.88 mmol, 2.00 equiv) was mixed, Pd 2 (dba) 3 (1.00 g, 1.08 mmol, 0.20 equiv) and [(t-Bu) 3 PH ]BF 4 (630 mg, 2.17 mmol, 0.4 equiv) was added. The resulting mixture was stirred at 60° C. for 8 h under a nitrogen atmosphere, the mixture cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with PE/EtOAc (1:2) to give 2,4-dimethoxy-5-[(1E)-3,3,3-trifluoroprop-1-ene- 1-yl] pyrimidine (890 mg, 66%) as a pale yellow solid. MS m/z: 235 [M+H] + .

단계 2: 2,4-디메톡시-5-(3,3,3-트리플루오로프로필)피리미딘의 합성Step 2: Synthesis of 2,4-dimethoxy-5-(3,3,3-trifluoropropyl)pyrimidine

상기 단계 1에서 수득된 화합물 (890 mg, 3.80 mmol, 1.00당량) 및 Pd/C (808 mg, 7.60 mmol, 2.00당량)를 MeOH (10 mL) 중에 혼합하고 수소 대기하에 25℃에서 10시간 동안 교반하였다. 고체를 여과하고, 여액을 감압 농축시켜서 2,4-디메톡시-5-(3,3,3-트리플루오로프로필)피리미딘 (700 mg, 75%)을 백색 고체로 수득하였다. MS m/z: 237 [M+H]+.The compound obtained in step 1 (890 mg, 3.80 mmol, 1.00 equiv) and Pd/C (808 mg, 7.60 mmol, 2.00 equiv) were mixed in MeOH (10 mL) and stirred at 25°C for 10 hours under a hydrogen atmosphere. did The solid was filtered and the filtrate was concentrated under reduced pressure to give 2,4-dimethoxy-5-(3,3,3-trifluoropropyl)pyrimidine (700 mg, 75%) as a white solid. MS m/z: 237 [M+H] + .

단계 3: 5-(3,3,3-트리플루오로프로필)피리미딘-2,4-디올의 합성Step 3: Synthesis of 5-(3,3,3-trifluoropropyl)pyrimidine-2,4-diol

상기 단계 2에서 수득된 화합물 (650 mg, 2.75 mmol, 1.00당량)을 MeOH (4 mL) 중에 교반 혼합하고, HCl (0.60 mL)을 질소 대기하에 25℃에서 적가하였다. 혼합물을 질소 대기하에 25℃에서 3일 동안 교반하고, 생성된 혼합물을 감압 농축시켰다. 조 생성물을 PE/EtOAc (10:1)로 세척하여 5-(3,3,3-트리플루오로프로필)피리미딘-2,4-디올 (500 mg, 83%)을 백색 고체로 수득하였다. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 10.98 (brs, 2H), 7.45 (s, 1H), 2.44 (s, 4H); MS m/z: 209 [M+H]+.The compound obtained in step 2 above (650 mg, 2.75 mmol, 1.00 equiv) was stirred and mixed in MeOH (4 mL), and HCl (0.60 mL) was added dropwise at 25°C under a nitrogen atmosphere. The mixture was stirred at 25° C. for 3 days under a nitrogen atmosphere, and the resulting mixture was concentrated under reduced pressure. The crude product was washed with PE/EtOAc (10:1) to give 5-(3,3,3-trifluoropropyl)pyrimidine-2,4-diol (500 mg, 83%) as a white solid. 1 H-NMR (DMSO-d 6 , 400 MHz) δ (ppm): 10.98 (brs, 2H), 7.45 (s, 1H), 2.44 (s, 4H); MS m/z: 209 [M+H] + .

단계 4: 2,4-디클로로-5-(3,3,3-트리플루오로프로필)피리미딘의 합성Step 4: Synthesis of 2,4-dichloro-5-(3,3,3-trifluoropropyl)pyrimidine

상기 단계 3에서 수득된 화합물 (480 mg, 2.30 mmol, 1.00당량)을 POCl3 (5 mL) 중에 교반 혼합하고, DIEA (894 mg, 6.91 mmol, 3.00당량)를 0℃에서 적가하였다. 생성된 혼합물을 100℃에서 16시간 동안 교반하였다. 혼합물을 얼음에 천천히 붓고, EtOAc (3×30 mL)로 추출하였다. 유기층을 모아서 무수 황산나트륨 상에서 건조하고 감압 농축시켰다. 조 생성물을 PE/EtOAc (10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2,4-디클로로-5-(3,3,3-트리플루오로프로필)피리미딘 (200 mg, 34%)을 연황색 오일로 수득하였다. MS m/z: 245/247/249 [M+H]+.The compound obtained in step 3 above (480 mg, 2.30 mmol, 1.00 equiv) was stirred and mixed in POCl 3 (5 mL), and DIEA (894 mg, 6.91 mmol, 3.00 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 100 °C for 16 hours. The mixture was poured slowly onto ice and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with PE/EtOAc (10:1) to give 2,4-dichloro-5-(3,3,3-trifluoropropyl)pyrimidine (200 mg, 34%) was obtained as a pale yellow oil. MS m/z: 245/247/249 [M+H] + .

제조예 6: 2,4-디클로로-5-(2,2,2-트리플루오로에틸)피리미딘Preparation Example 6: 2,4-dichloro-5- (2,2,2-trifluoroethyl) pyrimidine

Figure pct00066
Figure pct00066

단계 1: 에틸(2Z)-4,4,4-트리플루오로-2-(히드록시메틸리덴)부타노에이트의 합성Step 1: Synthesis of ethyl(2Z)-4,4,4-trifluoro-2-(hydroxymethylidene)butanoate

THF (50 mL) 중에 에틸 4,4,4-트리플루오로부타노에이트 (5.00g, 28.80 mmol, 1.00당량) 용액을 교반하고, 리튬 디이소프로필아미드(LDA)(3.99 mL, 37.20 mmol, 1.00당량)를 질소 대기하에 -40℃에서 적가하였다. 생성된 혼합물을 질소 대기하에 -40℃에서 1시간 동안 교반하였다. 상기 혼합물에 에틸 포메이트 (9.50 mL, 128.19 mmol, 4.00당량)을 -60℃에서 적가하였다. 생성된 혼합물을 밤새 실온에서 더 교반하였다. TLC는 반응이 완료되었음을 나타내었다. 0℃에서 NH4Cl 포화 수용액 (100 mL)을 첨가하여 반응을 ??칭시켰다. 생성된 혼합물을 EtOAc (3×100 mL)로 추출하고, 유기층을 모아서 염수 (3×100 mL)로 세척하여, 무수 Na2SO4 상에서 건조시켰다. 여과 후 여액을 감압 농축하여 에틸 (2Z)-4,4,4-트리플루오로-2-(히드록시메틸리덴)부타노에이트 (2.5g, 43.81%)를 황색 오일로 수득하였다.A solution of ethyl 4,4,4-trifluorobutanoate (5.00 g, 28.80 mmol, 1.00 equiv) in THF (50 mL) was stirred and added with lithium diisopropylamide (LDA) (3.99 mL, 37.20 mmol, 1.00 equivalent) was added dropwise at -40°C under a nitrogen atmosphere. The resulting mixture was stirred at -40 °C for 1 hour under a nitrogen atmosphere. Ethyl formate (9.50 mL, 128.19 mmol, 4.00 equiv) was added dropwise to the above mixture at -60 °C. The resulting mixture was further stirred overnight at room temperature. TLC showed the reaction to be complete. The reaction was quenched by the addition of saturated aqueous NH 4 Cl (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to obtain ethyl (2Z)-4,4,4-trifluoro-2-(hydroxymethylidene)butanoate (2.5 g, 43.81%) as a yellow oil.

단계 2: 5-(2,2,2-트리플루오로에틸)-1,3-디하이드로피리미딘-2,4-디온의 합성Step 2: Synthesis of 5-(2,2,2-trifluoroethyl)-1,3-dihydropyrimidine-2,4-dione

상기 단계 1에서 수득된 화합물 (2.50g, 12.61 mmol, 1.00당량)을 H2SO4 (25 mL) 중에 교반하고, 우레아 (0.76g, 12.61 mmol, 1.00당량)를 질소 대기하에 실온에서 첨가하였다. 생성된 혼합물을 질소 대기하에 70℃에서 밤새 교반하였다. LCMS는 반응이 완료되었음을 나타내었다. NaHCO3 포화 수용액으로 혼합물을 pH 8로 염기성화시켰다. 생성된 혼합물을 EtOAc (3×50 mL)로 추출하고, 유기층을 모아서 염수 (100 mL)로 세척하여, 무수 Na2SO4 상에서 건조시켰다. 여과 후 여액을 감압 농축시키고, 잔사를 CH2Cl2/MeOH (12:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 5-(2,2,2-트리플루오로에틸)-1,3-디하이드로피리미딘-2,4-디온 (300 mg, 12.25%)을 황백색 고체로 수득하였다. MS m/z: 195 [M+H]+.The compound obtained in step 1 above (2.50 g, 12.61 mmol, 1.00 equiv) was stirred in H 2 SO 4 (25 mL), and urea (0.76 g, 12.61 mmol, 1.00 equiv) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 70° C. under a nitrogen atmosphere. LCMS indicated the reaction was complete. The mixture was basified to pH 8 with saturated aqueous NaHCO 3 solution. The resulting mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with CH 2 Cl 2 /MeOH (12:1) and purified by silica gel column chromatography to obtain 5-(2,2,2-trifluoroethyl)-1,3- Dihydropyrimidine-2,4-dione (300 mg, 12.25%) was obtained as an off-white solid. MS m/z: 195 [M+H] + .

단계 3: 2,4-디클로로-5-(2,2,2-트리플루오로에틸)피리미딘의 합성Step 3: Synthesis of 2,4-dichloro-5-(2,2,2-trifluoroethyl)pyrimidine

상기 단계 2에서 수득된 화합물 (300 mg, 1.54 mmol, 1.00당량)을 POCl3 (3.00 mL) 중에 교반하고, DIEA(399 mg, 3.09 mmol, 2.00당량)를 질소 대기하에 0℃에서 적가하였다. 생성된 혼합물을 질소 대기하에 110℃에서 밤새 교반하였다. LCMS는 반응이 완료되었음을 나타내었다. 혼합물을 실온으로 냉각시키고, NaHCO3 포화 수용액으로 혼합물을 pH 8로 염기성화시켰다. 생성된 혼합물을 EtOAc (3×20 mL)로 추출하고, 유기층을 모아서 염수 (3×20 mL)로 세척하여, 무수 Na2SO4 상에서 건조시켰다. 여과 후 여액을 감압 농축하여 2,4-디클로로-5-(2,2,2-트리플루오로에틸)피리미딘 (150 mg, 42.02%)을 황색 오일로 수득하였다. MS m/z: 231/233/235 [M+H]+.The compound obtained in step 2 (300 mg, 1.54 mmol, 1.00 equiv) was stirred in POCl 3 (3.00 mL), and DIEA (399 mg, 3.09 mmol, 2.00 equiv) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred overnight at 110° C. under a nitrogen atmosphere. LCMS indicated the reaction was complete. The mixture was cooled to room temperature and the mixture was basified to pH 8 with saturated aqueous NaHCO 3 solution. The resulting mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (3×20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to obtain 2,4-dichloro-5-(2,2,2-trifluoroethyl)pyrimidine (150 mg, 42.02%) as a yellow oil. MS m/z: 231/233/235 [M+H] + .

실시예 1: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-3-메톡시페닐]피페리딘-3-올Example 1: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-methoxyphenyl]piperidin-3-ol

Figure pct00067
Figure pct00067

실시예 1의 화합물을 하기 반응식 1에 따라서 합성하였다.The compound of Example 1 was synthesized according to Scheme 1 below.

[반응식 1][Scheme 1]

Figure pct00068
Figure pct00068

단계 1: 1-(3-메톡시-4-니트로페닐)피페리딘-3-올의 합성Step 1: Synthesis of 1-(3-methoxy-4-nitrophenyl)piperidin-3-ol

아세토니트릴 (4 mL) 중의 3-히드록시피페리딘 (142 mg, 1.40 mmol, 1.2당량) 및 DIPEA (0.31 mL, 1.78 mmol, 1.5당량) 용액에 4-플루오로-2-메톡시-1-니트로벤젠 (200 mg, 1.17 mmol)을 첨가한 후 80℃에서 밤새 교반하였다. 반응 완료 후, 반응 혼합물을 증발시키고 컬럼 크로마토그래피로 정제하여 원하는 생성물을 밝은 황색(bright yellow) 분말 (209 mg, 0.96 mmol, 82% 수율)로 수득하였다. 1H NMR (400 MHz, Acetone-d6); δ 7.88 (d, J = 9.6 Hz, 1H), 6.58 (s, 1H), 6.56 (d, J = 8.4 Hz, 1H), 3.98 (d, J = 4.8 Hz, 1H), 3.94 (s, 3H), 3.89-3.85 (m, 1H), 3.77-3.73 (m, 2H), 3.18-3.12(m, 1H), 3.04 (dd, J = 12.8, 4.0 Hz, 1H), 2.04-1.99 (m, 1H), 1.88-1.85 (m, 1H), 1.61-1.54 (m, 2H).To a solution of 3-hydroxypiperidine (142 mg, 1.40 mmol, 1.2 equiv) and DIPEA (0.31 mL, 1.78 mmol, 1.5 equiv) in acetonitrile (4 mL) 4-fluoro-2-methoxy-1- Nitrobenzene (200 mg, 1.17 mmol) was added followed by stirring at 80 °C overnight. After completion of the reaction, the reaction mixture was evaporated and purified by column chromatography to give the desired product as a bright yellow powder (209 mg, 0.96 mmol, 82% yield). 1 H NMR (400 MHz, Acetone-d 6 ); δ 7.88 (d, J = 9.6 Hz, 1H), 6.58 (s, 1H), 6.56 (d, J = 8.4 Hz, 1H), 3.98 (d, J = 4.8 Hz, 1H), 3.94 (s, 3H) , 3.89-3.85 (m, 1H), 3.77-3.73 (m, 2H), 3.18-3.12 (m, 1H), 3.04 (dd, J = 12.8, 4.0 Hz, 1H), 2.04-1.99 (m, 1H) , 1.88–1.85 (m, 1H), 1.61–1.54 (m, 2H).

단계 2: 1-(4-아미노-3-메톡시페닐)피페리딘-3-올의 합성Step 2: Synthesis of 1-(4-amino-3-methoxyphenyl)piperidin-3-ol

상기 단계 1에서 수득된 화합물 (209 mg, 0.96 mmol)의 MeOH (15 mL) 용액에 탄소 상 10% 팔라듐 (40 mg)을 첨가하였다. 현탁액을 진공 하에 탈기하고 H2로 여러 번 퍼지(purge)하였다. 혼합물을 H2 하에 25℃에서 1시간 동안 교반하였다. 반응 완료 후, 혼합물을 셀라이트 패드를 통해 여과하고, 잔사를 증발시켜서 컬럼 크로마토그래피로 정제하여 원하는 생성물을 갈색 고체 (158 mg, 0.71 mmol, 74% 수율)로 수득하였다. 1H NMR (400 MHz, Acetone-d6); δ 6.57 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 6.35 (d, J = 8.4 Hz, 1H), 3.94 (brs, 2H), 3.80 (s, 3H), 3.74-3.69 (m, 2H), 3.38-3.35 (m, 1H), 3.18-3.15(m, 1H), 2.62-2.59(m, 1H), 2.49 (dd, J = 10.8, 2.4 Hz, 1H), 1.91-1.88 (m, 1H), 1.80-1.77 (m, 1H), 1.62-1.59 (m, 1H), 1.32-1.30 (m, 1H).To a solution of the compound obtained in step 1 above (209 mg, 0.96 mmol) in MeOH (15 mL) was added 10% palladium on carbon (40 mg). The suspension was degassed under vacuum and purged several times with H 2 . The mixture was stirred at 25° C. under H 2 for 1 hour. After completion of the reaction, the mixture was filtered through a celite pad and the residue was evaporated and purified by column chromatography to give the desired product as a brown solid (158 mg, 0.71 mmol, 74% yield). 1 H NMR (400 MHz, Acetone-d 6 ); δ 6.57 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 6.35 (d, J = 8.4 Hz, 1H), 3.94 (brs, 2H), 3.80 (s, 3H), 3.74–3.69 ( m, 2H), 3.38-3.35 (m, 1H), 3.18-3.15 (m, 1H), 2.62-2.59 (m, 1H), 2.49 (dd, J = 10.8, 2.4 Hz, 1H), 1.91-1.88 ( m, 1H), 1.80–1.77 (m, 1H), 1.62–1.59 (m, 1H), 1.32–1.30 (m, 1H).

단계 3: 1-(4-((4-클로로-5-(트리플루오로메틸)피리미딘-2-일)아미노)-3-메톡시페닐)피페리딘-3-올의 합성Step 3: Synthesis of 1-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-3-ol

DCE/t-BuOH (1:1, 6 mL) 중의 5-트리플루오로메틸-2,4-디클로로피리미딘 (108 mg, 0.5 mmol, 1.1당량) 용액에 염화아연 (에테르 중 1M 용액 2.2 mL, 2.2당량)을 0℃에서 첨가하였다. 1시간 후, 상기 단계 2에서 수득된 화합물 (101 mg, 1.0당량)을 첨가한 다음 DCE/t-BuOH (3 mL) 중의 트리에틸아민 (0.07 mL, 1.1당량) 용액을 적가하였다. 24시간 동안 교반한 후 반응 혼합물을 농축하고, 잔사를 EtOAc로 희석시켜서 물 및 NaHCO3 포화 수용액으로 세척하였다. 유기층을 무수 MgSO4 상에서 건조시킨 후, 잔사를 증발시키고 컬럼 크로마토그래피로 정제하여 원하는 생성물을 황색 고체 (78.9 mg, 0.20 mmol, 43% 수율)로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.54 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 6.68 (s, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.57 (s, 1H), 3.88 (s, 3H), 3.82-3.80 (m, 1H), 3.61-3.59 (m, 1H), 3.45-3.42(m, 1H), 2.81 (t, J = 10.0 Hz, 1H), 2.70 (dd, J = 11.2, 2.0 Hz, 1H), 2.01-1.99 (m, 1H), 1.92-1.89 (m, 1H), 1.72-1.68 (m, 1H), 1.48-1.42 (m, 1H).Zinc chloride (2.2 mL of a 1M solution in ether; 2.2 eq) was added at 0 °C. After 1 hour, the compound obtained in step 2 above (101 mg, 1.0 equiv.) was added followed by a solution of triethylamine (0.07 mL, 1.1 equiv.) in DCE/t-BuOH (3 mL) dropwise. After stirring for 24 hours the reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water and saturated aqueous NaHCO 3 . After drying the organic layer over anhydrous MgSO 4 , the residue was evaporated and purified by column chromatography to give the desired product as a yellow solid (78.9 mg, 0.20 mmol, 43% yield). 1 H NMR (400 MHz, CD 3 OD); δ 8.54 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 6.68 (s, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.57 (s, 1H), 3.88 (s, 3H), 3.82-3.80 (m, 1H), 3.61-3.59 (m, 1H), 3.45-3.42 (m, 1H), 2.81 (t, J = 10.0 Hz, 1H), 2.70 (dd, J = 11.2, 2.0 Hz, 1H), 2.01–1.99 (m, 1H), 1.92–1.89 (m, 1H), 1.72–1.68 (m, 1H), 1.48–1.42 (m, 1H).

단계 4: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-3-메톡시페닐]피페리딘-3-올(실시예 1의 화합물)의 합성Step 4: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl} Synthesis of amino)-3-methoxyphenyl]piperidin-3-ol (compound of Example 1)

아세토니트릴 (1 mL) 중의 (3S,4S)-3,4-디플루오로피롤리딘 (33.6 mg, 0.24 mmol, 1.2당량) 및 DIPEA (0.05 mL, 0.29 mmol, 1.5당량) 용액에 상기 단계 3에서 수득된 화합물 (78.9 mg, 0.20 mmol)을 첨가한 후 80℃에서 밤새 교반하였다. 반응 완료 후, 반응 혼합물을 증발시키고 컬럼 크로마토그래피로 정제하여 원하는 생성물(실시예 1의 화합물)을 갈색 분말 (25.6 mg, 0.06 mmol, 29% 수율)로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 8.31 (s, 1H), 8.18 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 6.48 (d, J = 8.0 Hz, 1H), 5.53 (brs, 1H), 5.40 (brs, 1H), 4.78 (brs, 1H), 3.98-3.83 (m, 4H), 3.79 (s, 3H), 3.59-3.56 (m, 2H), 3.47-3.44 (m, 1H), 2.64 (t, J = 11.2 Hz, 1H), 2.47 (m, 1H), 1.91-1.87 (m, 1H), 1.77-1.74 (m, 1H), 1.56-1.53 (m, 1H), 1.30-1.23 (m, 1H); MS m/z: 474 [M+H]+.Step 3 above to a solution of (3S,4S)-3,4-difluoropyrrolidine (33.6 mg, 0.24 mmol, 1.2 equiv) and DIPEA (0.05 mL, 0.29 mmol, 1.5 equiv) in acetonitrile (1 mL). After adding the compound obtained in (78.9 mg, 0.20 mmol), the mixture was stirred at 80°C overnight. After completion of the reaction, the reaction mixture was evaporated and purified by column chromatography to give the desired product (compound of Example 1) as a brown powder (25.6 mg, 0.06 mmol, 29% yield). 1 H NMR (400 MHz, DMSO-d 6 ); δ 8.31 (s, 1H), 8.18 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 6.48 (d, J = 8.0 Hz, 1H), 5.53 (brs, 1H), 5.40 (brs, 1H), 4.78 (brs, 1H), 3.98-3.83 (m, 4H), 3.79 (s, 3H), 3.59-3.56 (m, 2H), 3.47-3.44 (m, 1H) , 2.64 (t, J = 11.2 Hz, 1H), 2.47 (m, 1H), 1.91–1.87 (m, 1H), 1.77–1.74 (m, 1H), 1.56–1.53 (m, 1H), 1.30–1.23 (m, 1H); MS m/z: 474 [M+H] + .

실시예 2: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-3-에톡시페닐]피페리딘-3-올Example 2: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-ethoxyphenyl]piperidin-3-ol

Figure pct00069
Figure pct00069

실시예 1의 단계 1에서 4-플루오로-2-메톡시-1-니트로벤젠 대신에 4-플루오로-2-에톡시-1-니트로벤젠을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 실시예 2의 화합물을 갈색 고체로 수득하였다. 1H NMR (400 MHz, CD3OD); 8.23 (d, J = 8.8 Hz, 1H), 8.18 (s, 1H), 6.66 (s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.40 (brs, 1H), 5.27 (brs, 1H), 4.58 (s, 1H), 4.11 (q, J = 6.8 Hz, 2H), 4.05-3.81 (m, 3H), 3.79-3.77 (m, 2H), 3.56-3.54 (m, 1H), 3.40-3.37(m, 1H), 2.76 (t, J = 10.0 Hz, 1H), 2.66 (t, J = 11.2 Hz, 1H), 2.00-1.97 (m, 1H), 1.88-1.87 (m, 1H), 1.69-1.66 (m, 1H), 1.44-1.40 (m, 4H); MS m/z: 488 [M+H]+.In the same manner as in Example 1, except that 4-fluoro-2-ethoxy-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 2 was obtained as a brown solid. 1 H NMR (400 MHz, CD 3 OD); 8.23 (d, J = 8.8 Hz, 1H), 8.18 (s, 1H), 6.66 (s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.40 (brs, 1H), 5.27 (brs, 1H) ), 4.58 (s, 1H), 4.11 (q, J = 6.8 Hz, 2H), 4.05–3.81 (m, 3H), 3.79–3.77 (m, 2H), 3.56–3.54 (m, 1H), 3.40– 3.37(m, 1H), 2.76 (t, J = 10.0 Hz, 1H), 2.66 (t, J = 11.2 Hz, 1H), 2.00-1.97 (m, 1H), 1.88-1.87 (m, 1H), 1.69 -1.66 (m, 1H), 1.44-1.40 (m, 4H); MS m/z: 488 [M+H] + .

실시예 3: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-3-(프로판-2-일옥시)페닐]피페리딘-3-올Example 3: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-(propan-2-yloxy)phenyl]piperidin-3-ol

Figure pct00070
Figure pct00070

실시예 1의 단계 1에서 4-플루오로-2-메톡시-1-니트로벤젠 대신에 4-플루오로-2-이소프로폭시-1-니트로벤젠을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 실시예 3의 화합물을 담황색 고체로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.30 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 6.64 (d, J = 9.2 Hz, 1H), 5.43 (brs, 1H), 5.29 (brs, 1H), 4.69-4.63 (m, 1H), 4.57 (s, 1H), 4.08-4.00 (m, 4H), 3.82(m, 1H), 3.55-3.52 (m, 1H), 3.39-3.37(m, 1H), 2.76 (t, J = 10.8 Hz, 1H), 2.66 (t, J = 10.4 Hz, 1H), 2.01-1.98 (m, 1H), 1.92-1.89 (m, 1H), 1.74-1.66 (m, 1H), 1.46-1.44 (m, 1H), 1.41 (d, 6H); MS m/z: 502 [M+H]+.Same method as in Example 1, except that 4-fluoro-2-isopropoxy-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 3 was obtained as a pale yellow solid. 1 H NMR (400 MHz, CD 3 OD); δ 8.30 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 6.64 (d, J = 9.2 Hz, 1H), 5.43 (brs, 1H), 5.29 (brs, 1H), 4.69-4.63 (m, 1H), 4.57 (s, 1H), 4.08-4.00 (m, 4H), 3.82 (m, 1H), 3.55-3.52 (m, 1H), 3.39-3.37 (m, 1H), 2.76 (t, J = 10.8 Hz, 1H), 2.66 (t, J = 10.4 Hz, 1H), 2.01-1.98 (m, 1H), 1.92-1.89 (m, 1H), 1.74-1.66 (m , 1H), 1.46-1.44 (m, 1H), 1.41 (d, 6H); MS m/z: 502 [M+H] + .

실시예 4: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-3-(트리플루오로메톡시)페닐]피페리딘-3-올Example 4: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-(trifluoromethoxy)phenyl]piperidin-3-ol

Figure pct00071
Figure pct00071

실시예 1의 단계 1에서 4-플루오로-2-메톡시-1-니트로벤젠 대신에 4-플루오로-2-트리플루오로메톡시-1-니트로벤젠을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 실시예 4의 화합물을 백색 고체로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.27 (s, 1H), 8.23 (d, J = 9.2 Hz, 1H), 6.98-6.96 (m, 2H), 5.32 (brs, 1H), 5.19 (brs, 1H), 4.47 (brs, 1H), 4.04-3.91 (m, 4H), 3.82 (m, 1H), 2.96-2.94 (m, 1H), 2.78-2.75(m, 1H), 2.63 (t, J = 9.6 Hz, 1H), 2.54 (t, J = 9.6 Hz, 1H), 1.88-1.86 (m, 2H), 1.67-1.65 (m, 1H), 1.45-1.38 (m, 1H); MS m/z: 528 [M+H]+.Same as Example 1, except that 4-fluoro-2-trifluoromethoxy-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. In this way, the compound of Example 4 was obtained as a white solid. 1 H NMR (400 MHz, CD 3 OD); δ 8.27 (s, 1H), 8.23 (d, J = 9.2 Hz, 1H), 6.98-6.96 (m, 2H), 5.32 (brs, 1H), 5.19 (brs, 1H), 4.47 (brs, 1H), 4.04-3.91 (m, 4H), 3.82 (m, 1H), 2.96-2.94 (m, 1H), 2.78-2.75 (m, 1H), 2.63 (t, J = 9.6 Hz, 1H), 2.54 (t, J = 9.6 Hz, 1H), 1.88–1.86 (m, 2H), 1.67–1.65 (m, 1H), 1.45–1.38 (m, 1H); MS m/z: 528 [M+H] + .

실시예 5: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-3-(트리플루오로메틸)페닐]피페리딘-3-올Example 5: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-(trifluoromethyl)phenyl]piperidin-3-ol

Figure pct00072
Figure pct00072

실시예 1의 단계 1에서 4-플루오로-2-메톡시-1-니트로벤젠 대신에 4-플루오로-2-트리플루오로메틸-1-니트로벤젠을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 실시예 5의 화합물을 갈색 고체로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 8.54 (s, 1H), 7.04 (d, J= 8.4 Hz, 1H), 6.87 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.56 (brs, 1H), 5.43 (brs, 1H), 5.14 (m, 1H), 5.06 (s, 1H), 4.05-3.87 (m, 4H), 3.52-3.49 (m, 1H), 3.18-3.16 (m, 1H), 2.90-2.77(m, 2H), 2.07-2.05 (m, 1H), 1.84 (m, 1H), 1.69-1.61 (m, 2H); MS m/z: 512 [M+H]+.Same as Example 1, except that 4-fluoro-2-trifluoromethyl-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. In this way, the compound of Example 5 was obtained as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ); δ 8.54 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.56 (brs, 1H), 5.43 (brs, 1H), 5.14 (m, 1H), 5.06 (s, 1H), 4.05-3.87 (m, 4H), 3.52-3.49 (m, 1H), 3.18-3.16 (m, 1H), 2.90-2.77 (m, 2H), 2.07-2.05 (m, 1H), 1.84 (m, 1H), 1.69-1.61 (m, 2H); MS m/z: 512 [M+H] + .

실시예 6: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-3-메틸페닐]피페리딘-3-올Example 6: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-methylphenyl]piperidin-3-ol

Figure pct00073
Figure pct00073

실시예 1의 단계 1에서 4-플루오로-2-메톡시-1-니트로벤젠 대신에 4-플루오로-2-메틸-1-니트로벤젠을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 실시예 6의 화합물을 황색 고체로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 8.80 (s, 1H), 8.28 (s, 1H), 7.18 (m, 1H), 6.76 (s, 1H), 6.72 (d, J = 9.6 Hz, 1H), 5.50 (brs, 1H), 5.37 (brs, 1H), 4.78 (s, 1H), 3.88-3.77 (m, 4H), 3.57-3.54 (m, 2H), 3.45-3.42 (m, 1H), 2.63-2.58(m, 1H), 2.49-2.43 (m, 1H), 2.14 (m, 3H), 1.90-1.87 (m, 1H), 1.75-1.72 (m, 1H), 1.57-1.48 (m, 1H), 1.26-1.23 (m, 1H); MS m/z: 458 [M+H]+.Carried out in the same manner as in Example 1, except that 4-fluoro-2-methyl-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 6 was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ); δ 8.80 (s, 1H), 8.28 (s, 1H), 7.18 (m, 1H), 6.76 (s, 1H), 6.72 (d, J = 9.6 Hz, 1H), 5.50 (brs, 1H), 5.37 ( brs, 1H), 4.78 (s, 1H), 3.88-3.77 (m, 4H), 3.57-3.54 (m, 2H), 3.45-3.42 (m, 1H), 2.63-2.58 (m, 1H), 2.49- 2.43 (m, 1H), 2.14 (m, 3H), 1.90-1.87 (m, 1H), 1.75-1.72 (m, 1H), 1.57-1.48 (m, 1H), 1.26-1.23 (m, 1H); MS m/z: 458 [M+H] + .

실시예 7: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-3-에틸페닐]피페리딘-3-올Example 7: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-ethylphenyl]piperidin-3-ol

Figure pct00074
Figure pct00074

실시예 1의 단계 1에서 4-플루오로-2-메톡시-1-니트로벤젠 대신에 4-플루오로-2-에틸-1-니트로벤젠을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 실시예 7의 화합물을 갈색 고체로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.21 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.35 (brs, 1H), 5.21 (brs, 1H), 3.96-3.81 (m, 5H), 3.62-3.59 (m, 1H), 3.45-3.42 (m, 1H), 2.77 (t, J = 10.8 Hz, 1H), 2.69-2.59 (m, 3H), 2.02-1.99 (m, 1H), 1.92-1.89 (m, 1H), 1.72-1.69 (m, 1H), 1.44-1.41 (m, 1H), 1.18 (t, J = 7.6 Hz, 3H); MS m/z: 472 [M+H]+.Carried out in the same manner as in Example 1, except that 4-fluoro-2-ethyl-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 7 was obtained as a brown solid. 1 H NMR (400 MHz, CD 3 OD); δ 8.21 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.35 (brs, 1H), 5.21 (brs, 1H), 3.96-3.81 (m, 5H), 3.62-3.59 (m, 1H), 3.45-3.42 (m, 1H), 2.77 (t, J = 10.8 Hz, 1H), 2.69-2.59 (m, 3H) , 2.02–1.99 (m, 1H), 1.92–1.89 (m, 1H), 1.72–1.69 (m, 1H), 1.44–1.41 (m, 1H), 1.18 (t, J = 7.6 Hz, 3H); MS m/z: 472 [M+H] + .

실시예 8: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-3-[(프로판-2-일)아미노]페닐]피페리딘-3-올Example 8: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-3-[(propan-2-yl)amino]phenyl]piperidin-3-ol

Figure pct00075
Figure pct00075

실시예 1의 단계 1에서 4-플루오로-2-메톡시-1-니트로벤젠 대신에 4-플루오로-2-이소프로필아미노-1-니트로벤젠을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 실시예 8의 화합물을 자주색 고체로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.30 (s, 1H), 7.10 (brs, 1H), 6.42-6.38 (m, 2H), 5.34 (brs, 1H), 5.20 (brs, 1H), 3.96-3.81 (m, 5H), 3.68-3.57 (m, 2H), 3.43-3.41 (m, 1H), 2.81-2.76 (m, 1H), 2.71-2.66 (m, 1H), 2.00-1.89 (m, 2H), 1.73-1.68 (m, 1H), 1.46-1.38 (m, 1H), 1.19 (d, J = 6.0 Hz, 6H); MS m/z: 501 [M+H]+.Same method as Example 1, except that 4-fluoro-2-isopropylamino-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. to give the compound of Example 8 as a purple solid. 1 H NMR (400 MHz, CD 3 OD); δ 8.30 (s, 1H), 7.10 (brs, 1H), 6.42-6.38 (m, 2H), 5.34 (brs, 1H), 5.20 (brs, 1H), 3.96-3.81 (m, 5H), 3.68-3.57 (m, 2H), 3.43-3.41 (m, 1H), 2.81-2.76 (m, 1H), 2.71-2.66 (m, 1H), 2.00-1.89 (m, 2H), 1.73-1.68 (m, 1H) , 1.46–1.38 (m, 1H), 1.19 (d, J = 6.0 Hz, 6H); MS m/z: 501 [M+H] + .

실시예 9: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-2-플루오로-5-메톡시페닐]피페리딘-3-올Example 9: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-2-fluoro-5-methoxyphenyl]piperidin-3-ol

Figure pct00076
Figure pct00076

실시예 1의 단계 1에서 4-플루오로-2-메톡시-1-니트로벤젠 대신에 1,2-디플루오로-4-메톡시-5-니트로벤젠을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 실시예 9의 화합물을 백색 고체로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 8.39 (s, 1H), 8.27 (s, 1H), 7.75 (d, J = 14.4 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.56 (brs, 1H), 5.43 (brs, 1H), 4.82 (d, J = 4.8 Hz, 1H), 4.02-3.86 (m, 4H), 3.82 (s, 3H), 3.64-3.63 (m, 1H), 3.36-3.31 (m, 1H), 3.19-3.16 (m, 1H), 2.61 (t, J = 11.2 Hz, 1H), 2.45 (t, J = 10.0 Hz, 1H), 1.92-1.90 (m, 1H), 1.77-1.74 (m, 1H), 1.62-1.53 (m, 1H), 1.27-1.23 (m, 1H); MS m/z: 492 [M+H]+.Example 1 and Example 1, except that 1,2-difluoro-4-methoxy-5-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. In the same manner, the compound of Example 9 was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ); δ 8.39 (s, 1H), 8.27 (s, 1H), 7.75 (d, J = 14.4 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.56 (brs, 1H), 5.43 (brs, 1H), 4.82 (d, J = 4.8 Hz, 1H), 4.02-3.86 (m, 4H), 3.82 (s, 3H), 3.64-3.63 (m, 1H), 3.36-3.31 (m, 1H), 3.19 -3.16 (m, 1H), 2.61 (t, J = 11.2 Hz, 1H), 2.45 (t, J = 10.0 Hz, 1H), 1.92-1.90 (m, 1H), 1.77-1.74 (m, 1H), 1.62-1.53 (m, 1H), 1.27-1.23 (m, 1H); MS m/z: 492 [M+H] + .

실시예 10: 1-[2-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-5-(3-히드록시피페리딘-1-일)페닐]에탄-1-온Example 10: 1-[2-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)-5-(3-hydroxypiperidin-1-yl)phenyl]ethan-1-one

Figure pct00077
Figure pct00077

실시예 1의 단계 1에서 4-플루오로-2-메톡시-1-니트로벤젠 대신에 1-(5-플루오로-2-니트로페닐)에탄-1-온을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 실시예 10의 화합물을 밝은 황색 고체로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.44 (d, J = 9.2 Hz, 1H), 8.23 (s, 1H), 7.41 (s, 1H), 7.21 (d, J = 9.6 Hz, 1H), 5.33 (brs, 1H), 5.19 (brs, 1H), 3.40-3.90 (m, 4H), 3.72 (m, 1H), 3.47-3.44 (m, 1H), 3.31-3.28 (m, 1H), 2.74-2.71 (m, 1H), 2.63-2.58 (m, 1H), 2.55 (s, 3H), 1.91-1.81 (m, 2H), 1.62-1.59 (m, 1H), 1.35-1.32 (m, 1H); MS m/z: 486 [M+H]+.Example 1, except that 1-(5-fluoro-2-nitrophenyl)ethan-1-one was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 10 was obtained as a light yellow solid in the same manner as above. 1 H NMR (400 MHz, CD 3 OD); δ 8.44 (d, J = 9.2 Hz, 1H), 8.23 (s, 1H), 7.41 (s, 1H), 7.21 (d, J = 9.6 Hz, 1H), 5.33 (brs, 1H), 5.19 (brs, 1H), 3.40-3.90 (m, 4H), 3.72 (m, 1H), 3.47-3.44 (m, 1H), 3.31-3.28 (m, 1H), 2.74-2.71 (m, 1H), 2.63-2.58 ( m, 1H), 2.55 (s, 3H), 1.91-1.81 (m, 2H), 1.62-1.59 (m, 1H), 1.35-1.32 (m, 1H); MS m/z: 486 [M+H] + .

실시예 11: 2-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)-5-(3-히드록시피페리딘-1-일)벤조니트릴Example 11: 2-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl}amino) -5-(3-hydroxypiperidin-1-yl)benzonitrile

Figure pct00078
Figure pct00078

실시예 1의 단계 1에서 4-플루오로-2-메톡시-1-니트로벤젠 대신에 5-플루오로-2-니트로벤조니트릴을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 실시예 11의 화합물을 담황색 고체로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.46 (s, 1H), 7.13 (d, J = 9.2 Hz, 1H), 6.97 (s, 1H), 6.79 (d, J = 9.2 Hz, 1H), 5.31 (brs, 1H), 5.25 (brs, 1H), 5.24-5.23 (m, 1H), 4.11-3.98 (m, 4H), 3.56-3.53 (m, 1H), 3.22-3.19 (m, 1H), 3.00-2.95 (m, 1H), 2.91-2.86 (m, 1H), 2.17-2.14 (m, 1H), 2.01-1.98 (m, 1H), 1.86-1.78 (m, 2H); MS m/z: 469 [M+H]+.Example 11 was prepared in the same manner as in Example 1, except that 5-fluoro-2-nitrobenzonitrile was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound was obtained as a pale yellow solid. 1 H NMR (400 MHz, CD 3 OD); δ 8.46 (s, 1H), 7.13 (d, J = 9.2 Hz, 1H), 6.97 (s, 1H), 6.79 (d, J = 9.2 Hz, 1H), 5.31 (brs, 1H), 5.25 (brs, 1H), 5.24-5.23 (m, 1H), 4.11-3.98 (m, 4H), 3.56-3.53 (m, 1H), 3.22-3.19 (m, 1H), 3.00-2.95 (m, 1H), 2.91- 2.86 (m, 1H), 2.17-2.14 (m, 1H), 2.01-1.98 (m, 1H), 1.86-1.78 (m, 2H); MS m/z: 469 [M+H] + .

실시예 12: 1-[3-클로로-4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 12: 1-[3-chloro-4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidine -2-yl}amino)phenyl]piperidin-3-ol

Figure pct00079
Figure pct00079

실시예 1의 단계 1에서 4-플루오로-2-메톡시-1-니트로벤젠 대신에 4-플루오로-2-클로로-1-니트로벤젠을 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 실시예 12의 화합물을 백색 고체로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 8.91 (s, 1H), 8.32 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.12 (brs, 1H), 5.38 (brs, 1H), 4.82 (brs, 1H), 3.89-3.78 (m, 4H), 3.59-3.56 (m, 2H), 3.49-3.46 (m, 1H), 2.72 (t, J = 10.8 Hz, 1H), 2.58 (t, J = 11.2 Hz, 1H), 1.89-1.87 (m, 1H), 1.76-1.73 (m, 1H), 1.56-1.47 (m, 1H), 1.34-1.29 (m, 1H); MS m/z: 478 [M+H]+.Carried out in the same manner as in Example 1, except that 4-fluoro-2-chloro-1-nitrobenzene was used instead of 4-fluoro-2-methoxy-1-nitrobenzene in Step 1 of Example 1. The compound of Example 12 was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ); δ 8.91 (s, 1H), 8.32 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J = 8.8 Hz, 1H), 5.12 (brs, 1H), 5.38 (brs, 1H), 4.82 (brs, 1H), 3.89-3.78 (m, 4H), 3.59-3.56 (m, 2H), 3.49-3.46 (m, 1H), 2.72 (t, J = 10.8 Hz, 1H), 2.58 (t, J = 11.2 Hz, 1H), 1.89-1.87 (m, 1H), 1.76-1.73 (m, 1H), 1.56-1.47 (m, 1H), 1.34-1.29 (m , 1H); MS m/z: 478 [M+H] + .

실시예 13: 4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-N-[2-메톡시-4-(모르폴린-4-일)페닐]-5-(트리플루오로메틸)피리미딘-2-아민Example 13: 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-N-[2-methoxy-4-(morpholin-4-yl)phenyl]- 5-(trifluoromethyl)pyrimidin-2-amine

Figure pct00080
Figure pct00080

실시예 1의 단계 1에서 3-히드록시피페리딘 대신에 모르폴린을 사용한 것으로 제외하고 실시예 1과 동일한 방법으로 실시예 13의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 8.32 (s, 1H), 8.22 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.53 (brs, 1H), 5.40 (brs, 3H), 3.98-3.84 (m, 4H), 3.80 (s, 3H), 3.76-3.74 (m, 4H), 3.12-3.10 (m, 4H); MS m/z: 460 [M+H]+.The compound of Example 13 was obtained as a white powder in the same manner as in Example 1, except that morpholine was used instead of 3-hydroxypiperidine in Step 1 of Example 1. 1 H NMR (400 MHz, DMSO-d 6 ); δ 8.32 (s, 1H), 8.22 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.53 (brs, 1H), 5.40 (brs, 3H), 3.98-3.84 (m, 4H), 3.80 (s, 3H), 3.76-3.74 (m, 4H), 3.12-3.10 (m, 4H); MS m/z: 460 [M+H] + .

실시예 14: 1-(4-{[4-(2,3-디메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 14: 1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidine -3-ol

Figure pct00081
Figure pct00081

실시예 14의 화합물을 하기 반응식 2에 따라서 합성하였다.The compound of Example 14 was synthesized according to Scheme 2 below.

[반응식 2][Scheme 2]

Figure pct00082
Figure pct00082

단계 1: 1-(4-니트로페닐)피페리딘-3-올의 합성Step 1: Synthesis of 1-(4-nitrophenyl)piperidin-3-ol

아세토니트릴 (14 mL) 중의 3-히드록시피페리딘 (753.6 mg, 7.45 mmol, 1.05당량) 및 DIPEA (1.3 mL, 7.45 mmol, 1.05당량) 용액에 1-플루오로-4-니트로벤젠 (1.0g, 7.09 mmol)을 첨가한 후 80℃에서 밤새 교반하였다. 반응 완료 후, 반응 혼합물을 증발시키고 컬럼 크로마토그래피 (CH2Cl2:메탄올 = 20:1)로 정제하여 원하는 생성물을 황색 분말 (1.54 g, 6.92 mmol, 99% 수율)로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 8.02 (d, J = 9.6 Hz, 2H), 6.96 (d, J = 9.6 Hz, 2H), 4.92 (s, 1H), 3.80-3.77 (m, 1H), 3.73-3.70 (m, 1H), 3.56(m, 1H), 3.16-3.11 (m, 1H), 3.01 (dd, J = 12.8, 4.4 Hz, 1H), 1.89-1.87 (m, 1H), 1.77-1.75 (m, 1H), 1.47-1.41 (m, 2H).1-fluoro-4-nitrobenzene (1.0 g , 7.09 mmol) was added and stirred overnight at 80 °C. After completion of the reaction, the reaction mixture was evaporated and purified by column chromatography (CH 2 Cl 2 :methanol = 20:1) to give the desired product as a yellow powder (1.54 g, 6.92 mmol, 99% yield). 1 H NMR (400 MHz, DMSO-d 6 ); δ 8.02 (d, J = 9.6 Hz, 2H), 6.96 (d, J = 9.6 Hz, 2H), 4.92 (s, 1H), 3.80–3.77 (m, 1H), 3.73–3.70 (m, 1H), 3.56(m, 1H), 3.16-3.11 (m, 1H), 3.01 (dd, J = 12.8, 4.4 Hz, 1H), 1.89-1.87 (m, 1H), 1.77-1.75 (m, 1H), 1.47- 1.41 (m, 2H).

단계 2: 1-(4-아미노페닐)피페리딘-3-올의 합성Step 2: Synthesis of 1-(4-aminophenyl)piperidin-3-ol

상기 단계 1에서 수득된 화합물 (577 mg, 2.60 mmol)의 MeOH (15 mL) 용액에 탄소 상 10% 팔라듐 (80 mg)을 첨가하였다. 현탁액을 진공 하에 탈기하고 H2로 여러 번 퍼지하였다. 혼합물을 H2 하에 25℃에서 1시간 동안 교반하였다. 반응 완료 후, 혼합물을 셀라이트 패드를 통해 여과하고, 잔사를 증발시켜서 컬럼 크로마토그래피 (CH2Cl2:메탄올 = 20:1)로 정제하여 원하는 생성물을 갈색 고체 (473 mg, 2.31 mmol, 89% 수율)로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 6.65 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 8.4 Hz, 1H), 4.68 (d, J = 4.4 Hz, 1H), 4.53 (brs, NH2), 3.59-3.55 (m, 1H), 3.29-3.26 (m, 1H), 3.14-3.12(m, 1H), 2.43-2.38 (m, 1H), 2.29-2.24 (m, 1H), 1.85-1.83 (m, 1H), 1.72-1.69 (m, 1H), 1.56-1.47 (m, 1H), 1.21-1.16 (m, 1H).To a solution of the compound obtained in step 1 above (577 mg, 2.60 mmol) in MeOH (15 mL) was added 10% palladium on carbon (80 mg). The suspension was degassed under vacuum and purged several times with H 2 . The mixture was stirred at 25° C. under H 2 for 1 hour. After completion of the reaction, the mixture was filtered through a celite pad, and the residue was evaporated and purified by column chromatography (CH 2 Cl 2 :methanol = 20:1) to give the desired product as a brown solid (473 mg, 2.31 mmol, 89% yield) was obtained. 1 H NMR (400 MHz, DMSO-d 6 ); δ 6.65 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 8.4 Hz, 1H), 4.68 (d, J = 4.4 Hz, 1H), 4.53 (brs, NH2), 3.59–3.55 (m, 1H), 3.29-3.26 (m, 1H), 3.14-3.12 (m, 1H), 2.43-2.38 (m, 1H), 2.29-2.24 (m, 1H), 1.85-1.83 (m, 1H), 1.72- 1.69 (m, 1H), 1.56–1.47 (m, 1H), 1.21–1.16 (m, 1H).

단계 3: 1-(4-((4-클로로-5-(트리플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-3-올의 합성Step 3: Synthesis of 1-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidin-3-ol

CH2Cl2/t-BuOH (1:1, 6 mL) 중의 5-트리플루오로메틸-2,4-디클로로피리미딘 (500 mg, 2.32 mmol, 1.0당량) 용액에 염화아연 (에테르 중 1M 용액 2.3 mL, 1.0당량)을 0℃에서 첨가하였다. 1시간 후, 상기 단계 2에서 수득된 화합물 (445 mg, 2.32 mmol, 1.0당량)을 첨가한 다음 CH2Cl2/t-BuOH (6 mL) 중의 트리에틸아민 (0.36 mL, 2.55 mmol, 1.1당량) 용액을 적가하였다. 1.5시간 동안 교반한 후 반응 혼합물을 농축시키고, 잔사를 EtOAc로 희석하여 물 및 NaHCO3 포화 수용액으로 세척하였다. 유기층을 무수 MgSO4 상에서 건조시킨 후, 잔사를 증발시키고 컬럼 크로마토그래피 (CH2Cl2:메탄올 = 20:1)로 정제하여 원하는 생성물을 황색 고체 (877 mg, 2.30 mmol, 97% 수율)로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 10.40 (s, 1H), 8.70 (s, 1H), 7.45 (d, J = 7.6 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.80 (d, J = 4.4 Hz, 1H), 3.60-3.53 (m, 2H), 3.44-3.41(m, 1H), 2.64-2.58 (m, 1H), 2.50-2.44 (m, 1H), 1.89-1.87 (m, 1H), 1.76-1.72 (m, 1H), 1.57-1.48 (m, 1H), 1.30-1.20 (m, 1H).To a solution of 5-trifluoromethyl-2,4-dichloropyrimidine (500 mg, 2.32 mmol, 1.0 equiv) in CH 2 Cl 2 /t-BuOH (1:1, 6 mL) was added zinc chloride (1M solution in ether). 2.3 mL, 1.0 eq) was added at 0 °C. After 1 hour, the compound from step 2 above (445 mg, 2.32 mmol, 1.0 equiv) was added followed by triethylamine (0.36 mL, 2.55 mmol, 1.1 equiv) in CH 2 Cl 2 /t-BuOH (6 mL). ) solution was added dropwise. After stirring for 1.5 h, the reaction mixture was concentrated, and the residue was diluted with EtOAc and washed with water and saturated aqueous NaHCO 3 . After the organic layer was dried over anhydrous MgSO 4 , the residue was evaporated and purified by column chromatography (CH 2 Cl 2 :methanol = 20:1) to give the desired product as a yellow solid (877 mg, 2.30 mmol, 97% yield). did 1 H NMR (400 MHz, DMSO-d 6 ); δ 10.40 (s, 1H), 8.70 (s, 1H), 7.45 (d, J = 7.6 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.80 (d, J = 4.4 Hz, 1H) ( m, 1H), 1.57–1.48 (m, 1H), 1.30–1.20 (m, 1H).

단계 4: 1-(4-((4-(2,3-디메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-3-올(실시예 14의 화합물)의 합성Step 4: 1-(4-((4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine- Synthesis of 3-ol (Compound of Example 14)

아세토니트릴 (1.5 mL) 중의 2,3-디메틸피롤리딘 염산염 (21.5 mg, 0.16 mmol, 1.2당량) 및 DIPEA (0.04 mL, 0.20 mmol. 1.5당량) 용액에 상기 단계 3에서 수득된 화합물 (50 mg, 0.13 mmol, 1.0당량)을 첨가한 후 60℃에서 밤새 교반하였다. 반응 완료 후, 반응 혼합물을 증발시키고 컬럼 크로마토그래피 (헥산:에틸아세테이트 = 1:1)로 정제하여 원하는 생성물(실시예 14의 화합물)을 백색 분말 (32.6 mg, 0.75 mmol, 55% 수율)로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.19 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.64 (m, 0.5H), 3.99 (m, 0.5H), 3.81-3.77 (m, 1.5H), 3.62-3.60 (m, 1H), 3.53-3.50(m, 1.5H), 3.36-3.33(m, 1H), 2.71 (t, 1H), 2.60 (dd, J = 11.2, 2.0 Hz, 1H), 2.32-2.21 (m, 0.5H), 2.18-1.80 (m, 4H), 1.70 (m, 1H), 1.58-1.49 (m, 0.5H), 1.42-1.35 (m, 1H), 1.28 (d, J = 6.0 Hz, 1.5H), 1.09-1.06 (m, 4.5H); MS m/z: 436 [M+H]+.The compound obtained in step 3 above (50 mg , 0.13 mmol, 1.0 equiv) was added and stirred overnight at 60°C. After completion of the reaction, the reaction mixture was evaporated and purified by column chromatography (hexane:ethyl acetate = 1:1) to obtain the desired product (compound of Example 14) as a white powder (32.6 mg, 0.75 mmol, 55% yield). did 1 H NMR (400 MHz, CD 3 OD); δ 8.19 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.64 (m, 0.5H), 3.99 (m, 0.5H), 3.81- 3.77 (m, 1.5H), 3.62-3.60 (m, 1H), 3.53-3.50 (m, 1.5H), 3.36-3.33 (m, 1H), 2.71 (t, 1H), 2.60 (dd, J = 11.2 , 2.0 Hz, 1H), 2.32-2.21 (m, 0.5H), 2.18-1.80 (m, 4H), 1.70 (m, 1H), 1.58-1.49 (m, 0.5H), 1.42-1.35 (m, 1H) ), 1.28 (d, J = 6.0 Hz, 1.5H), 1.09–1.06 (m, 4.5H); MS m/z: 436 [M+H] + .

실시예 15 및 16: (3R)-1-(4-{[4-(2,3-디메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올 및 (3S)-1-(4-{[4-(2,3-디메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Examples 15 and 16: (3R)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino }phenyl)piperidin-3-ol and (3S)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine- 2-yl]amino}phenyl)piperidin-3-ol

Figure pct00083
Figure pct00084
Figure pct00083
Figure pct00084

실시예 14의 화합물을 분리 정제하여 (3R)-1-(4-{[4-(2,3-디메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올 및 (3S)-1-(4-{[4-(2,3-디메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올을 각각 백색 분말로 수득하였다.The compound of Example 14 was isolated and purified to obtain (3R)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- yl]amino}phenyl)piperidin-3-ol and (3S)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl) Pyrimidin-2-yl]amino}phenyl)piperidin-3-ol was obtained as a white powder, respectively.

(3R)-1-(4-{[4-(2,3-디메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올(실시예 15의 화합물)(3R)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidine -3-ol (compound of Example 15)

1H NMR (400 MHz, CD3OD); δ 8.18 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.64 (m, 0.5H), 3.99 (m, 0.5H), 3.81-3.76 (m, 1.5H), 3.61-3.60 (m, 1H), 3.53-3.49(m, 1.5H), 3.36-3.35(m, 1H), 2.73 (t, J = 10.4 Hz, 1H), 2.60 (dd, J = 11.2, 2.0 Hz, 1H), 2.32-2.20 (m, 0.5H), 2.17-1.79 (m, 4H), 1.72-1.66 (m, 1H), 1.58-1.49 (m, 0.5H), 1.42-1.35 (m, 1H), 1.27 (d, J = 6.4 Hz, 1.5H), 1.12-1.05 (m, 4.5H); MS m/z: 436 [M+H]+. 1 H NMR (400 MHz, CD 3 OD); δ 8.18 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.64 (m, 0.5H), 3.99 (m, 0.5H), 3.81- ( dd, J = 11.2, 2.0 Hz, 1H), 2.32-2.20 (m, 0.5H), 2.17-1.79 (m, 4H), 1.72-1.66 (m, 1H), 1.58-1.49 (m, 0.5H), 1.42–1.35 (m, 1H), 1.27 (d, J = 6.4 Hz, 1.5H), 1.12–1.05 (m, 4.5H); MS m/z: 436 [M+H] + .

(3S)-1-(4-{[4-(2,3-디메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올(실시예 16의 화합물)(3S)-1-(4-{[4-(2,3-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidine -3-ol (compound of Example 16)

1H NMR (400 MHz, CD3OD); δ 8.19 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.64 (m, 0.5H), 3.98 (m, 0.5H), 3.81-3.76 (m, 1.5H), 3.61-3.59 (m, 1H), 3.53-3.50(m, 1.5H), 3.36(m, 1H), 2.71 (t, J = 11.2 Hz, 1H), 2.60 (dd, J = 10.8 Hz, 1H), 2.32-2.20 (m, 0.5H), 2.17-1.79 (m, 4H), 1.70 (m, 1H), 1.58-1.49 (m, 0.5H), 1.42-1.35 (m, 1H), 1.27 (d, J = 6.4 Hz, 1.5H), 1.12-1.05 (m, 4.5H); MS m/z: 436 [M+H]+. 1 H NMR (400 MHz, CD 3 OD); δ 8.19 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.64 (m, 0.5H), 3.98 (m, 0.5H), 3.81- 3.76 (m, 1.5H), 3.61-3.59 (m, 1H), 3.53-3.50 (m, 1.5H), 3.36 (m, 1H), 2.71 (t, J = 11.2 Hz, 1H), 2.60 (dd, J = 10.8 Hz, 1H), 2.32–2.20 (m, 0.5H), 2.17–1.79 (m, 4H), 1.70 (m, 1H), 1.58–1.49 (m, 0.5H), 1.42–1.35 (m, 1H), 1.27 (d, J = 6.4 Hz, 1.5H), 1.12–1.05 (m, 4.5H); MS m/z: 436 [M+H] + .

실시예 17: 1-(4-{[4-(3-메틸피페리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 17: 1-(4-{[4-(3-methylpiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3 -all

Figure pct00085
Figure pct00085

실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 3-메틸피페리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 17의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 8.21 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.57-4.56 (m, 1H), 3.83-3.78 (m, 2H), 3.54-3.50 (m, 1H), 3.24 (m, 1H), 2.74-2.71 (m, 1H), 2.60 (dd, J = 11.2, 2.0 Hz, 1H), 1.99-1.96 (m, 1H), 1.91-1.58 (m, 9H), 1.40-1.29 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H); MS m/z: 436 [M+H]+.The compound of Example 17 was obtained as a white powder in the same manner as in Example 14, except that 3-methylpiperidine was used instead of 2,3-dimethylpyrrolidine hydrochloride in Step 4 of Example 14. 1 H NMR (400 MHz, DMSO-d 6 ); δ 8.21 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.57–4.56 (m, 1H), 3.83–3.78 (m, 2H), 3.54-3.50 (m, 1H), 3.24 (m, 1H), 2.74-2.71 (m, 1H), 2.60 (dd, J = 11.2, 2.0 Hz, 1H), 1.99-1.96 (m, 1H), 1.91- 1.58 (m, 9H), 1.40–1.29 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H); MS m/z: 436 [M+H] + .

실시예 18: 1-(4-{[4-(3,5-디메틸피페리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 18: 1-(4-{[4-(3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidine -3-ol

Figure pct00086
Figure pct00086

실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 3,5-디메틸피페리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 18의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 9.45 (brs, 1H), 8.30 (s, 1H), 7.49 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.78 (d, J = 4.4 Hz, 1H), 4.05-4.01 (m, 2H), 3.61-3.58 (m, 1H), 3.51-3.47 (m, 1H), 3.38-3.34 (m, 1H), 2.60-2.48 (m, 3H), 2.42 (dd, J = 11.2, 2.0 Hz, 1H), 1.85 (m, 1H), 1.77-1.72 (m, 2H), 1.66-1.42 (m, 3H), 1.25-1.21 (m, 1H), 0.87 (d, J = 6.8 Hz, 6H), 0.86-0.84 (m, 1H); MS m/z: 450 [M+H]+.The compound of Example 18 was obtained as a white powder in the same manner as in Example 14, except that 3,5-dimethylpiperidine was used instead of 2,3-dimethylpyrrolidine hydrochloride in Step 4 of Example 14. . 1 H NMR (400 MHz, DMSO-d 6 ); δ 9.45 (brs, 1H), 8.30 (s, 1H), 7.49 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.78 (d, J = 4.4 Hz, 1H) , 4.05-4.01 (m, 2H), 3.61-3.58 (m, 1H), 3.51-3.47 (m, 1H), 3.38-3.34 (m, 1H), 2.60-2.48 (m, 3H), 2.42 (dd, J = 11.2, 2.0 Hz, 1H), 1.85 (m, 1H), 1.77-1.72 (m, 2H), 1.66-1.42 (m, 3H), 1.25-1.21 (m, 1H), 0.87 (d, J = 6.8 Hz, 6H), 0.86-0.84 (m, 1H); MS m/z: 450 [M+H] + .

실시예 19: 1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 19: 1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3 -all

Figure pct00087
Figure pct00087

실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 2-메틸피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 19의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.18 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.83-3.76 (m, 4H), 3.70-3.65 (m, 1H), 3.53-3.49 (m, 1H), 3.22-3.17(m, 1H), 2.71 (m, 1H), 2.63-2.58 (m, 1H), 2.36-2.32 (m, 1H), 2.12-2.11 (m, 1H), 2.00-1.96 (m, 1H), 1.90-1.86 (m, 1H), 1.71-1.56 (m, 2H), 1.40 (m, 1H), 1.13 (d, J = 6.4 Hz, 3H); MS m/z: 422 [M+H]+.The compound of Example 19 was obtained as a white powder in the same manner as in Example 14, except that 2-methylpyrrolidine was used instead of 2,3-dimethylpyrrolidine hydrochloride in Step 4 of Example 14. 1 H NMR (400 MHz, CD 3 OD); δ 8.18 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.83-3.76 (m, 4H), 3.70-3.65 (m, 1H), 3.53-3.49 (m, 1H), 3.22-3.17 (m, 1H), 2.71 (m, 1H), 2.63-2.58 (m, 1H), 2.36-2.32 (m, 1H), 2.12-2.11 (m, 1H) ), 2.00–1.96 (m, 1H), 1.90–1.86 (m, 1H), 1.71–1.56 (m, 2H), 1.40 (m, 1H), 1.13 (d, J = 6.4 Hz, 3H); MS m/z: 422 [M+H] + .

실시예 20: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 20: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)phenyl]piperidin-3-ol

Figure pct00088
Figure pct00088

실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 (3S,4S)-3,4-디플루오로피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 20의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 9.52 (brs, 1H), 8.35 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.56 (brs, 1H), 5.42 (brs, 1H), 4.77 (d, J = 4.0 Hz, 1H), 4.04-3.85 (m, 4H), 3.59-3.50 (m, 2H), 3.40-3.37 (m, 1H), 2.58 (t, J = 10.8 Hz, 1H), 2.46-2.41 (m, 1H), 1.89-1.87 (m, 1H), 1.76-1.73 (m, 1H), 1.55-1.52 (m, 1H), 1.27-1.20 (m, 1H); MS m/z: 444 [M+H]+.Example 20 in the same manner as in Example 14, except that (3S,4S)-3,4-difluoropyrrolidine was used instead of 2,3-dimethylpyrrolidine hydrochloride in step 4 of Example 14. The compound of was obtained as a white powder. 1 H NMR (400 MHz, DMSO-d 6 ); δ 9.52 (brs, 1H), 8.35 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.56 (brs, 1H), 5.42 (brs, 1H), 4.77 (d, J = 4.0 Hz, 1H), 4.04-3.85 (m, 4H), 3.59-3.50 (m, 2H), 3.40-3.37 (m, 1H), 2.58 (t, J = 10.8 Hz) , 1H), 2.46-2.41 (m, 1H), 1.89-1.87 (m, 1H), 1.76-1.73 (m, 1H), 1.55-1.52 (m, 1H), 1.27-1.20 (m, 1H); MS m/z: 444 [M+H] + .

실시예 21: (3S)-1-(4-{[4-(모르폴린-4-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 21: (3S)-1-(4-{[4-(morpholin-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3 -all

Figure pct00089
Figure pct00089

실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 모르폴린을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 21의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.29 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.83-3.78 (m, 5H), 3.62 (m, 4H), 3.56-3.52 (m, 1H), 3.39-3.36 (m, 1H), 2.73 (t, J = 10.4 Hz, 1H), 2.62 (dd, J = 11.2, 2.4 Hz, 1H), 2.02-1.98 (m, 1H), 1.92-1.87 (m, 1H), 1.71-1.68 (m, 1H), 1.42-1.39 (m, 1H); MS m/z: 424 [M+H]+.The compound of Example 21 was obtained as a white powder in the same manner as in Example 14, except that morpholine was used instead of 2,3-dimethylpyrrolidine hydrochloride in Step 4 of Example 14. 1 H NMR (400 MHz, CD 3 OD); δ 8.29 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.83–3.78 (m, 5H), 3.62 (m, 4H), 3.56– 3.52 (m, 1H), 3.39–3.36 (m, 1H), 2.73 (t, J = 10.4 Hz, 1H), 2.62 (dd, J = 11.2, 2.4 Hz, 1H), 2.02–1.98 (m, 1H) , 1.92-1.87 (m, 1H), 1.71-1.68 (m, 1H), 1.42-1.39 (m, 1H); MS m/z: 424 [M+H] + .

실시예 22 및 23: (3R)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올 및 (3S)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Examples 22 and 23: (3R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl ]amino}phenyl)piperidin-3-ol and (3S)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl )pyrimidin-2-yl]amino}phenyl)piperidin-3-ol

Figure pct00090
Figure pct00091
Figure pct00090
Figure pct00091

실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 3,3-디플루오로피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 라세미체를 수득하고, 이로부터 (3R)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올 및 (3S)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올을 각각 백색 분말로 분리 정제하였다.A racemate was obtained in the same manner as in Example 14, except that 3,3-difluoropyrrolidine was used instead of 2,3-dimethylpyrrolidine hydrochloride in step 4 of Example 14, from which (3R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol and (3S)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- yl]amino}phenyl)piperidin-3-ol was isolated and purified as a white powder.

(3R)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올(실시예 22의 화합물)(3R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol (compound of Example 22)

1H NMR (400 MHz, DMSO-d6); δ 9.51 (brs, 1H), 8.35 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.76 (d, J = 4.8 Hz, 1H), 3.96 (t, J = 12.8 Hz, 2H), 3.84-3.81 (m, 2H), 3.60-3.50 (m, 2H), 3.40-3.37 (m, 1H), 2.60-2.52 (m, 3H), 2.46-2.41 (m, 1H), 1.89-1.86 (m, 1H), 1.75-1.72 (m, 1H), 1.57-1.48 (m, 1H), 1.27 (m, 1H); MS m/z: 444 [M+H]+. 1 H NMR (400 MHz, DMSO-d 6 ); δ 9.51 (brs, 1H), 8.35 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.76 (d, J = 4.8 Hz, 1H) , 3.96 (t, J = 12.8 Hz, 2H), 3.84–3.81 (m, 2H), 3.60–3.50 (m, 2H), 3.40–3.37 (m, 1H), 2.60–2.52 (m, 3H), 2.46 -2.41 (m, 1H), 1.89-1.86 (m, 1H), 1.75-1.72 (m, 1H), 1.57-1.48 (m, 1H), 1.27 (m, 1H); MS m/z: 444 [M+H] + .

(3S)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올(실시예 23의 화합물)(3S)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol (compound of Example 23)

1H NMR (400 MHz, CD3OD); δ 8.27 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 4.01-3.90 (m, 4H), 3.81-3.77 (m, 1H), 3.54-3.51 (m, 1H), 3.37-3.34 (m, 1H), 2.72 (t, J = 11.6 Hz, 1H), 2.61 (dd, J = 10.4 Hz, 1H), 2.53-2.44 (m, 2H), 2.00-1.96 (m, 1H), 1.90-1.86 (m, 1H), 1.70-1.67 (m, 1H), 1.41-1.37 (m, 1H); MS m/z: 444 [M+H]+. 1 H NMR (400 MHz, CD 3 OD); δ 8.27 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 4.01–3.90 (m, 4H), 3.81–3.77 (m, 1H), 3.54-3.51 (m, 1H), 3.37-3.34 (m, 1H), 2.72 (t, J = 11.6 Hz, 1H), 2.61 (dd, J = 10.4 Hz, 1H), 2.53-2.44 (m, 2H) , 2.00-1.96 (m, 1H), 1.90-1.86 (m, 1H), 1.70-1.67 (m, 1H), 1.41-1.37 (m, 1H); MS m/z: 444 [M+H] + .

실시예 24: (3S,5R)-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3,5-디올Example 24: (3S,5R)-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl )piperidine-3,5-diol

Figure pct00092
Figure pct00092

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 (3S,5R)-피페리딘-3,5-디올을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 2-메틸피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 24의 화합물을 회색 분말로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.23 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 3.84-3.78 (m, 4H), 3.70-3.58 (m, 3H), 3.20 (t, J = 9.2 Hz, 1H), 2.51 (t, J = 10.4 Hz, 2H), 2.39-2.29(m, 2H), 2.13-2.11 (m, 1H), 1.64-1.55 (m, 1H), 1.41-1.32 (m, 1H), 1.13 (d, J = 6.4 Hz, 3H); MS m/z: 438 [M+H]+.In step 1 of Example 14, (3S,5R)-piperidine-3,5-diol was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, 2,3-dimethylpyrrolidine The compound of Example 24 was obtained as a gray powder in the same manner as in Example 14, except that 2-methylpyrrolidine was used instead of hydrochloride. 1 H NMR (400 MHz, CD 3 OD); δ 8.23 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 3.84–3.78 (m, 4H), 3.70–3.58 (m, 3H), 3.20 (t, J = 9.2 Hz, 1H), 2.51 (t, J = 10.4 Hz, 2H), 2.39-2.29 (m, 2H), 2.13-2.11 (m, 1H), 1.64-1.55 (m, 1H) , 1.41–1.32 (m, 1H), 1.13 (d, J = 6.4 Hz, 3H); MS m/z: 438 [M+H] + .

실시예 24(R): (3S,5R)-1-(4-{[4-((R)-2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3,5-디올Example 24(R): (3S,5R)-1-(4-{[4-((R)-2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine- 2-yl]amino}phenyl)piperidine-3,5-diol

Figure pct00093
Figure pct00093

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 (3S,5R)-피페리딘-3,5-디올을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 (R)-2-메틸피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 24(R)의 화합물을 미황색 분말로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 9.31 (brs, 1H), 8.27 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.92 (m, 2H), 4.51-4.49 (m, 1H), 3.58-3.55 (m, 6H), 2.30 (t, J = 11.2 Hz, 2H), 2.18-1.99 (m, 3H), 1.85-1.77 (m, 1H), 1.61-1.58 (m, 1H), 1.22 (d, J = 6.0 Hz, 3H), 1.22-1.18 (m, 1H); MS m/z: 438 [M+H]+.In step 1 of Example 14, (3S,5R)-piperidine-3,5-diol was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, 2,3-dimethylpyrrolidine The compound of Example 24(R) was obtained as a pale yellow powder in the same manner as in Example 14, except that (R)-2-methylpyrrolidine was used instead of hydrochloride. 1 H NMR (400 MHz, DMSO-d 6 ); δ 9.31 (brs, 1H), 8.27 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.92 (m, 2H), 4.51–4.49 ( m, 1H), 3.58-3.55 (m, 6H), 2.30 (t, J = 11.2 Hz, 2H), 2.18-1.99 (m, 3H), 1.85-1.77 (m, 1H), 1.61-1.58 (m, 1H), 1.22 (d, J = 6.0 Hz, 3H), 1.22–1.18 (m, 1H); MS m/z: 438 [M+H] + .

실시예 24(S): (3S,5R)-1-(4-{[4-((S)-2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3,5-디올Example 24(S): (3S,5R)-1-(4-{[4-((S)-2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine- 2-yl]amino}phenyl)piperidine-3,5-diol

Figure pct00094
Figure pct00094

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 (3S,5R)-피페리딘-3,5-디올을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 (S)-2-메틸피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 24(S)의 화합물을 미황색 분말로 수득하였다. 1H NMR (400 MHz, Acetone-d6); δ 8.34 (brs, 1H), 8.25 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 4.62-4.59 (m, 1H), 4.03 (m, 1H), 3.83 (m, 2H), 3.66-3.64 (m, 1H), 3.54-3.51 (m, 3H), 2.67 (t, J = 10.4 Hz, 2H), 2.24-2.10 (m, 3H), 1.93-1.89 (m, 1H), 1.67-1.63 (m, 1H), 1.48-1.44 (m, 1H), 1.28 (d, J = 6.0 Hz, 3H); MS m/z 438 [M+H]+.In step 1 of Example 14, (3S,5R)-piperidine-3,5-diol was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, 2,3-dimethylpyrrolidine The compound of Example 24(S) was obtained as a pale yellow powder in the same manner as in Example 14, except that (S)-2-methylpyrrolidine was used instead of hydrochloride. 1 H NMR (400 MHz, Acetone-d 6 ); δ 8.34 (brs, 1H), 8.25 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 4.62–4.59 (m, 1H), 4.03 ( m, 1H), 3.83 (m, 2H), 3.66-3.64 (m, 1H), 3.54-3.51 (m, 3H), 2.67 (t, J = 10.4 Hz, 2H), 2.24-2.10 (m, 3H) , 1.93–1.89 (m, 1H), 1.67–1.63 (m, 1H), 1.48–1.44 (m, 1H), 1.28 (d, J = 6.0 Hz, 3H); MS m/z 438 [M+H] + .

실시예 25: 1-[2-({4-[(3S,5R)-3,5-디히드록시피페리딘-1-일]페닐}아미노)-5-(트리플루오로메틸)피리미딘-4-일]-3-메틸피페리딘-4-온Example 25: 1-[2-({4-[(3S,5R)-3,5-dihydroxypiperidin-1-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidine -4-yl] -3-methylpiperidin-4-one

Figure pct00095
Figure pct00095

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 (3S,5R)-피페리딘-3,5-디올을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 3-메틸피페리딘-4-온을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 25의 화합물을 황색 고체로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.32 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.35-4.32 (m, 2H), 3.82-3.77 (m, 2H), 3.63-3.60 (m, 2H), 3.54-3.48 (m, 1H), 3.10 (t, J = 12.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.65-2.59(m, 1H), 2.53-2.41 (m, 3H), 2.33-2.30 (m, 1H), 1.40-1.32 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H); MS m/z: 466 [M+H]+.In step 1 of Example 14, (3S,5R)-piperidine-3,5-diol was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, 2,3-dimethylpyrrolidine The compound of Example 25 was obtained as a yellow solid in the same manner as in Example 14, except that 3-methylpiperidin-4-one was used instead of hydrochloride. 1 H NMR (400 MHz, CD 3 OD); δ 8.32 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.35–4.32 (m, 2H), 3.82–3.77 (m, 2H), 3.63-3.60 (m, 2H), 3.54-3.48 (m, 1H), 3.10 (t, J = 12.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.65-2.59 (m, 1H), 2.53- 2.41 (m, 3H), 2.33–2.30 (m, 1H), 1.40–1.32 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H); MS m/z: 466 [M+H] + .

실시예 26: (3R)-1-(2-{[4-(3-메틸피페리딘-1-일)페닐]아미노}-5-(트리플루오로메틸)피리미딘-4-일)피롤리딘-3-올Example 26: (3R)-1-(2-{[4-(3-methylpiperidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)p Rolidin-3-ol

Figure pct00096
Figure pct00096

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 3-메틸피페리딘을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 (R)-피롤리딘-3-올을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 26의 화합물을 연분홍색 분말로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 9.37 (s, 1H), 8.27 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 9.2 Hz, 2H), 5.04 (d, J = 2.8 Hz, 1H), 4.37 (brs, 1H), 3.76-3.64 (m, 4H), 3.47-3.44 (m, 1H), 3.08-3.05(m, 1H), 2.85-2.80(m, 1H), 1.99-1.96 (m, 1H), 1.90-1.88 (m, 1H), 1.80-1.49 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H); MS m/z: 422 [M+H]+.In step 1 of Example 14, 3-methylpiperidine was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, (R)-pyrroli was used instead of 2,3-dimethylpyrrolidine hydrochloride. Except for using din-3-ol, the compound of Example 26 was obtained as a pale pink powder in the same manner as in Example 14. 1 H NMR (400 MHz, DMSO-d 6 ); δ 9.37 (s, 1H), 8.27 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 9.2 Hz, 2H), 5.04 (d, J = 2.8 Hz, 1H) , 4.37 (brs, 1H), 3.76-3.64 (m, 4H), 3.47-3.44 (m, 1H), 3.08-3.05 (m, 1H), 2.85-2.80 (m, 1H), 1.99-1.96 (m, 1H), 1.90–1.88 (m, 1H), 1.80–1.49 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H); MS m/z: 422 [M+H] + .

실시예 27: (3S)-1-(2-{[4-(3-메틸피페리딘-1-일)페닐]아미노}-5-(트리플루오로메틸)피리미딘-4-일)피롤리딘-3-올Example 27: (3S)-1-(2-{[4-(3-methylpiperidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)p Rolidin-3-ol

Figure pct00097
Figure pct00097

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 3-메틸피페리딘을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 (S)-피롤리딘-3-올을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 27의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 9.37 (s, 1H), 8.27 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.03 (d, J = 2.4 Hz, 1H), 4.37 (brs, 1H), 3.76-3.64 (m, 4H), 3.47-3.44 (m, 1H), 3.08-3.05(m, 1H), 2.85-2.80(m, 1H), 1.99-1.96 (m, 1H), 1.89-1.88 (m, 1H), 1.76-1.49 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H); MS m/z: 422 [M+H]+.In step 1 of Example 14, 3-methylpiperidine was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, (S)-pyrroli was used instead of 2,3-dimethylpyrrolidine hydrochloride. The compound of Example 27 was obtained as a white powder in the same manner as in Example 14, except that din-3-ol was used. 1 H NMR (400 MHz, DMSO-d 6 ); δ 9.37 (s, 1H), 8.27 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.03 (d, J = 2.4 Hz, 1H) , 4.37 (brs, 1H), 3.76-3.64 (m, 4H), 3.47-3.44 (m, 1H), 3.08-3.05 (m, 1H), 2.85-2.80 (m, 1H), 1.99-1.96 (m, 1H), 1.89–1.88 (m, 1H), 1.76–1.49 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H); MS m/z: 422 [M+H] + .

실시예 28: 4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-N-[4-(3,5-디메틸피페리딘-1-일)페닐]-5-(트리플루오로메틸)피리미딘-2-아민Example 28: 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-N-[4-(3,5-dimethylpiperidin-1-yl)phenyl] -5-(trifluoromethyl)pyrimidin-2-amine

Figure pct00098
Figure pct00098

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 3,5-디메틸피페리딘을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 (3S,4S)-3,4-디플루오로피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 28의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.27 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 5.39 (brs, 1H), 5.25 (brs, 1H), 4.04-3.96 (m, 4H), 3.56-3.53 (m, 2H), 2.16 (t, J = 11.2 Hz, 2H), 1.83-1.81(m, 3H), 0.96 (d, J = 6.0 Hz, 6H), 0.69 (q, J = 12.4 Hz, 1H); MS m/z: 456 [M+H]+.In step 1 of Example 14, 3,5-dimethylpiperidine was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, 2,3-dimethylpyrrolidine hydrochloride (3S,4S The compound of Example 28 was obtained as a white powder in the same manner as in Example 14, except that )-3,4-difluoropyrrolidine was used. 1 H NMR (400 MHz, CD 3 OD); δ 8.27 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 5.39 (brs, 1H), 5.25 (brs, 1H), 4.04–3.96 ( m, 4H), 3.56-3.53 (m, 2H), 2.16 (t, J = 11.2 Hz, 2H), 1.83-1.81 (m, 3H), 0.96 (d, J = 6.0 Hz, 6H), 0.69 (q , J = 12.4 Hz, 1H); MS m/z: 456 [M+H] + .

실시예 29: (3R,4R)-1-(2-{[4-(3,5-디메틸피페리딘-1-일)페닐]아미노}-5-(트리플루오로메틸)피리미딘-4-일)-4-플루오로피페리딘-3-올Example 29: (3R,4R)-1-(2-{[4-(3,5-dimethylpiperidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidine-4 -yl) -4-fluoropiperidin-3-ol

Figure pct00099
Figure pct00099

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 3,5-디메틸피페리딘을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 (3R,4R)-4-플루오로피페리딘-3-올을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 29의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.26 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.54-4.53 (m, 0.5H), 4.42-4.41 (m, 0.5H), 4.12-4.08 (m, 1H), 4.00-3.96 (m, 1H), 3.73-3.71 (m, 1H), 3.54-3.51 (m, 2H), 3.24 (t, J = 11.6 Hz, 1H), 3.07 (dd, J = 13.2, 4.0 Hz, 1H), 2.21- 2.12(m, 3H), 1.82-1.70 (m, 4H), 0.95 (d, J = 6.0 Hz, 6H), 0.67 (q, J = 12.4 Hz, 1H); MS m/z: 468 [M+H]+.In step 1 of Example 14, 3,5-dimethylpiperidine was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, 2,3-dimethylpyrrolidine hydrochloride (3R,4R The compound of Example 29 was obtained as a white powder in the same manner as in Example 14, except that )-4-fluoropiperidin-3-ol was used. 1 H NMR (400 MHz, CD 3 OD); δ 8.26 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.54–4.53 (m, 0.5H), 4.42–4.41 (m, 0.5H) ), 4.12-4.08 (m, 1H), 4.00-3.96 (m, 1H), 3.73-3.71 (m, 1H), 3.54-3.51 (m, 2H), 3.24 (t, J = 11.6 Hz, 1H), 3.07 (dd, J = 13.2, 4.0 Hz, 1H), 2.21-2.12 (m, 3H), 1.82-1.70 (m, 4H), 0.95 (d, J = 6.0 Hz, 6H), 0.67 (q, J = 12.4 Hz, 1H); MS m/z: 468 [M+H] + .

실시예 30: 4-메틸-1-(4-{[4-(4-메틸피페리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 30: 4-methyl-1-(4-{[4-(4-methylpiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol

Figure pct00100
Figure pct00100

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 4-메틸피페리딘-3-올을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 4-메틸피페리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 30의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.21 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.22-4.18 (m, 2H), 3.68-3.66 (m, 1H), 3.65-3.53 (m, 1H), 2.98 (t, J = 12.8 Hz, 2H), 2.61 (t, J = 10.8 Hz, 1H), 2.43 (t, J = 10.8 Hz, 1H), 1.81-1.67 (m, 4H), 1.42-1.40 (m, 2H), 1.29-1.20 (m, 3H), 1.09 (d, J = 4.8 Hz, 3H), 0.97 (d, J = 6.0 Hz, 3H); MS m/z: 450 [M+H]+.4-methylpiperidin-3-ol was used instead of 3-hydroxypiperidine in step 1 of Example 14, and 4-methylpiperidin-3-ol was used instead of 2,3-dimethylpyrrolidine hydrochloride in step 4 of Example 14. The compound of Example 30 was obtained as a white powder in the same manner as in Example 14, except that methylpiperidine was used. 1 H NMR (400 MHz, CD 3 OD); δ 8.21 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.22-4.18 (m, 2H), 3.68-3.66 (m, 1H), 3.65-3.53 (m, 1H), 2.98 (t, J = 12.8 Hz, 2H), 2.61 (t, J = 10.8 Hz, 1H), 2.43 (t, J = 10.8 Hz, 1H), 1.81-1.67 (m , 4H), 1.42–1.40 (m, 2H), 1.29–1.20 (m, 3H), 1.09 (d, J = 4.8 Hz, 3H), 0.97 (d, J = 6.0 Hz, 3H); MS m/z: 450 [M+H] + .

실시예 31: (3R)-1-(2-{[4-(모르폴린-4-일)페닐]아미노}-5-(트리플루오로메틸)피리미딘-4-일)피롤리딘-3-올Example 31: (3R)-1-(2-{[4-(morpholin-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)pyrrolidin-3 -all

Figure pct00101
Figure pct00101

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 모르폴린을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 (R)-피롤리딘-3-올을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 31의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 9.39 (brs, 1H), 8.27 (s, 1H), 7.60 (brs, 2H), 6.89 (brs, 2H), 5.03 (brs, 1H), 4.37 (brs, 1H), 3.73-3.65 (m, 7H), 3.46-3.44 (m, 1H), 3.04 (m, 4H), 2.00-1.88 (m, 2H); MS m/z: 410 [M+H]+.In step 1 of Example 14, morpholine was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, (R)-pyrrolidine-3- instead of 2,3-dimethylpyrrolidine hydrochloride. The compound of Example 31 was obtained as a white powder in the same manner as in Example 14, except that ol was used. 1 H NMR (400 MHz, DMSO-d 6 ); δ 9.39 (brs, 1H), 8.27 (s, 1H), 7.60 (brs, 2H), 6.89 (brs, 2H), 5.03 (brs, 1H), 4.37 (brs, 1H), 3.73-3.65 (m, 7H) ), 3.46-3.44 (m, 1H), 3.04 (m, 4H), 2.00-1.88 (m, 2H); MS m/z: 410 [M+H] + .

실시예 32: (3S)-1-(2-{[4-(모르폴린-4-일)페닐]아미노}-5-(트리플루오로메틸)피리미딘-4-일)피롤리딘-3-올Example 32: (3S)-1-(2-{[4-(morpholin-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)pyrrolidin-3 -all

Figure pct00102
Figure pct00102

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 모르폴린을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 (S)-피롤리딘-3-올을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 32의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 9.39 (brs, 1H), 8.27 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.04 (s, 1H), 4.37 (s, 1H), 3.74-3.62 (m, 7H), 3.47-3.44 (m, 1H), 3.05-3.02 (m, 4H), 1.99-1.88 (m, 2H); MS m/z: 410 [M+H]+.In step 1 of Example 14, morpholine was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, (S)-pyrrolidine-3- instead of 2,3-dimethylpyrrolidine hydrochloride. The compound of Example 32 was obtained as a white powder in the same manner as in Example 14, except that ol was used. 1 H NMR (400 MHz, DMSO-d 6 ); δ 9.39 (brs, 1H), 8.27 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.04 (s, 1H), 4.37 (s, 1H), 3.74-3.62 (m, 7H), 3.47-3.44 (m, 1H), 3.05-3.02 (m, 4H), 1.99-1.88 (m, 2H); MS m/z: 410 [M+H] + .

실시예 33: 4-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)페닐]모르폴린-3-온Example 33: 4-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)phenyl]morpholin-3-one

Figure pct00103
Figure pct00103

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 모르폴린-3-온을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 (3S,4S)-3,4-디플루오로피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 33의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 9.85 (s, 1H), 8.43 (s, 1H), 7.74 (d, J = 7.2 Hz, 2H), 7.32 (d, J = 7.2 Hz, 2H), 5.57 (brs, 1H), 5.44 (brs, 1H), 4.19 (s, 2H), 4.08-3.88 (m, 5H), 3.72-3.69(m, 2H); MS m/z: 444 [M+H]+.In step 1 of Example 14, morpholin-3-one was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, (3S,4S)- The compound of Example 33 was obtained as a white powder in the same manner as in Example 14, except that 3,4-difluoropyrrolidine was used. 1 H NMR (400 MHz, DMSO-d 6 ); δ 9.85 (s, 1H), 8.43 (s, 1H), 7.74 (d, J = 7.2 Hz, 2H), 7.32 (d, J = 7.2 Hz, 2H), 5.57 (brs, 1H), 5.44 (brs, 1H), 4.19 (s, 2H), 4.08-3.88 (m, 5H), 3.72-3.69 (m, 2H); MS m/z: 444 [M+H] + .

실시예 34 및 35: (3R)-1-(4-{[4-(3-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피롤리딘-3-올 및 (3S)-1-(4-{[4-(3-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피롤리딘-3-올Examples 34 and 35: (3R)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl )pyrrolidin-3-ol and (3S)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl] amino} phenyl) pyrrolidin-3-ol

Figure pct00104
Figure pct00105
Figure pct00104
Figure pct00105

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 3-히드록시피롤리딘을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 3-메틸피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 화합물 1-(4-{[4-(3-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피롤리딘-3-올을 제조하였다.In step 1 of Example 14, 3-hydroxypyrrolidine was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, 3-methylpyrrolidine was used instead of 2,3-dimethylpyrrolidine hydrochloride. Compound 1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- was prepared in the same manner as in Example 14, except that Dean was used. yl]amino}phenyl)pyrrolidin-3-ol was prepared.

1-(4-{[4-(3-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피롤리딘-3-올을 분리 정제하여 (3R)-1-(4-{[4-(3-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피롤리딘-3-올 및 (3S)-1-(4-{[4-(3-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피롤리딘-3-올을 각각 백색 분말로 수득하였다.Isolate 1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrrolidin-3-ol (3R)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrrolidine -3-ol and (3S)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl) Pyrrolidin-3-ol was obtained as a white powder, respectively.

(3R)-1-(4-{[4-(3-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피롤리딘-3-올(실시예 34의 화합물)(3R)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrrolidin-3 -ol (compound of Example 34)

1H NMR (400 MHz, DMSO-d6); δ 8.16 (s, 1H), 8.06 (brs, 1H), 7.34 (d, J = 9.2 Hz, 2H), 6.46 (d, J = 8.8 Hz, 2H), 4.40 (m, 1H), 3.69 (m, 1H), 3.57-3.55 (m, 1H), 3.42-3.25 (m, 4H), 3.06 (d, J = 9.6 Hz, 1H), 2.97 (m, 0.5H), 2.85 (m, 0.5H), 2.28-2.25 (m, 1H), 2.06-2.00 (m, 2H), 1.91-1.86 (m, 1H), 1.52-1.48 (m, 1H), 1.03-1.02 (m, 3H); MS m/z: 408 [M+H]+. 1 H NMR (400 MHz, DMSO-d 6 ); δ 8.16 (s, 1H), 8.06 (brs, 1H), 7.34 (d, J = 9.2 Hz, 2H), 6.46 (d, J = 8.8 Hz, 2H), 4.40 (m, 1H), 3.69 (m, 1H), 3.57-3.55 (m, 1H), 3.42-3.25 (m, 4H), 3.06 (d, J = 9.6 Hz, 1H), 2.97 (m, 0.5H), 2.85 (m, 0.5H), 2.28 -2.25 (m, 1H), 2.06-2.00 (m, 2H), 1.91-1.86 (m, 1H), 1.52-1.48 (m, 1H), 1.03-1.02 (m, 3H); MS m/z: 408 [M+H] + .

(3S)-1-(4-{[4-(3-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피롤리딘-3-올(실시예 35의 화합물)(3S)-1-(4-{[4-(3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrrolidin-3 -ol (compound of Example 35)

1H NMR (400 MHz, Acetone-d6); δ 8.16 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.34 (brs, 1H), 6.52 (d, J = 8.8 Hz, 2H), 4.54 (m, 1H), 4.04 (m, 1H), 3.80-3.55 (m, 2H), 3.51-3.39 (m, 4H), 3.33-3.31 (m, 1H), 3.19-3.17 (m, 1H), 3.10-2.90 (m, 1H), 2.40-2.25 (m, 1H), 2.14-2.00 (m, 2H), 1.61-1.50 (m, 1H), 1.09-1.07 (m, 3H); MS m/z: 408 [M+H]+. 1 H NMR (400 MHz, Acetone-d 6 ); δ 8.16 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.34 (brs, 1H), 6.52 (d, J = 8.8 Hz, 2H), 4.54 (m, 1H), 4.04 (m, 1H), 3.80-3.55 (m, 2H), 3.51-3.39 (m, 4H), 3.33-3.31 (m, 1H), 3.19-3.17 (m, 1H), 3.10-2.90 (m, 1H), 2.40- 2.25 (m, 1H), 2.14-2.00 (m, 2H), 1.61-1.50 (m, 1H), 1.09-1.07 (m, 3H); MS m/z: 408 [M+H] + .

실시예 36: 1-(2-{[4-(3-메틸피롤리딘-1-일)페닐]아미노}-5-(트리플루오로메틸)피리미딘-4-일)아제티딘-3-올Example 36: 1-(2-{[4-(3-methylpyrrolidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)azetidin-3- all

Figure pct00106
Figure pct00106

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 3-메틸피롤리딘을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 아제티딘-3-올을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 36의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, Acetone-d6); δ 8.26 (brs, 1H), 8.14 (s, 1H), 7.58 (d, 2H), 6.51 (d, J = 8.8 Hz, 2H), 4.82 (m, 1H), 4.72 (m, 1H), 4.47-4.43 (m, 2H), 4.03-4.00 (m, 2H), 3.45-3.41 (m, 1H), 3.35-3.24 (m, 2H), 2.42-2.37 (m, 1H), 2.18-2.12 (m, 1H), 1.67-1.58 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H); MS m/z: 394 [M+H]+.3-methylpyrrolidine was used instead of 3-hydroxypiperidine in step 1 of Example 14, and azetidin-3-ol was used instead of 2,3-dimethylpyrrolidine hydrochloride in step 4 of Example 14. The compound of Example 36 was obtained as a white powder in the same manner as in Example 14, except that was used. 1 H NMR (400 MHz, Acetone-d 6 ); δ 8.26 (brs, 1H), 8.14 (s, 1H), 7.58 (d, 2H), 6.51 (d, J = 8.8 Hz, 2H), 4.82 (m, 1H), 4.72 (m, 1H), 4.47- 4.43 (m, 2H), 4.03-4.00 (m, 2H), 3.45-3.41 (m, 1H), 3.35-3.24 (m, 2H), 2.42-2.37 (m, 1H), 2.18-2.12 (m, 1H) ), 1.67–1.58 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H); MS m/z: 394 [M+H] + .

실시예 37: 1-(2-{[4-(2-메틸-1,4-옥사제판-4-일)페닐]아미노}-5-(트리플루오로메틸)피리미딘-4-일)아제티딘-3-올Example 37: 1-(2-{[4-(2-methyl-1,4-oxazepan-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)ase Thidin-3-ol

Figure pct00107
Figure pct00107

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 2-메틸-1,4-옥사제판을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 아제티딘-3-올을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 37의 화합물을 황색 고체로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.08 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 4.64-4.62 (m, 1H), 4.47-4.43 (m, 2H), 4.03-3.83 (m, 6H), 3.43-3.36(m, 3H), 3.00 (dd, J = 15.2, 4.8 Hz, 1H), 2.15-2.13 (m, 1H), 1.96-1.94 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H); MS m/z: 424 [M+H]+.In step 1 of Example 14, 2-methyl-1,4-oxazepane was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, azetidine was used instead of 2,3-dimethylpyrrolidine hydrochloride. Except for using -3-ol, the compound of Example 37 was obtained as a yellow solid in the same manner as in Example 14. 1 H NMR (400 MHz, CD 3 OD); δ 8.08 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 4.64–4.62 (m, 1H), 4.47–4.43 (m, 2H), 4.03-3.83 (m, 6H), 3.43-3.36 (m, 3H), 3.00 (dd, J = 15.2, 4.8 Hz, 1H), 2.15-2.13 (m, 1H), 1.96-1.94 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H); MS m/z: 424 [M+H] + .

실시예 38: 4-아미노-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 38: 4-amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol

Figure pct00108
Figure pct00108

단계 1: 4-(tert-부톡시카르보닐아미노)-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올의 합성Step 1: 4-(tert-butoxycarbonylamino)-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- Synthesis of yl]amino}phenyl)piperidin-3-ol

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 tert-부틸 (3-히드록시피페리딘-4-일)카르바메이트를 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 2-메틸피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 4-(tert-부톡시카르보닐아미노)-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올을 수득하였다.In step 1 of Example 14, tert -butyl (3-hydroxypiperidin-4-yl)carbamate was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, 2,3- 4-( tert -butoxycarbonylamino)-1-(4-{[4-(2- Methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3-ol was obtained.

단계 2: 4-아미노-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올(실시예 38의 화합물)의 합성Step 2: 4-Amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperi Synthesis of din-3-ol (compound of Example 38)

상기 단계 1에서 수득된 화합물(0.22 mmol, 1.0당량)의 CH2Cl2 (3 mL) 용액에 트리플루오로아세트산 (0.33 mL, 4.32 mmol, 20당량)을 첨가하고, 혼합물을 실온에서 3시간 동안 교반하였다. 혼합물을 NaHCO3 포화 용액으로 중화시키고, CH2Cl2로 추출하였다. 유기층을 모아서 MgSO4 상에서 건조하고, 여과하고 감압 농축하였다. 잔사를 컬럼 크로마토그래피(CH2Cl2:메탄올=10:1)로 정제하여 4-아미노-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올(실시예 38의 화합물)을 담황색 고체로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.21 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.85-3.74 (m, 3H), 3.69-3.61 (m, 3H), 3.22 (t, 1H), 2.87(m, 1H), 2.76 (t, J = 9.6 Hz, 1H), 2.57 (dd, J = 11.6, 1.2 Hz, 1H), 2.40-2.30 (m, 1H), 2.19-2.05 (m, 2H), 1.76-1.73 (m, 1H), 1.64-1.58 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H); MS m/z: 437 [M+H]+.Trifluoroacetic acid (0.33 mL, 4.32 mmol, 20 equiv) was added to a solution of the compound obtained in step 1 (0.22 mmol, 1.0 equiv) in CH 2 Cl 2 (3 mL), and the mixture was stirred at room temperature for 3 hours. Stir. The mixture was neutralized with saturated NaHCO 3 solution and extracted with CH 2 Cl 2 . The combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (CH 2 Cl 2 :methanol=10:1) to obtain 4-amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(tri) Obtained fluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3-ol (compound of Example 38) as a pale yellow solid. 1 H NMR (400 MHz, CD 3 OD); δ 8.21 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.85-3.74 (m, 3H), 3.69-3.61 (m, 3H), 3.22 (t, 1H), 2.87 (m, 1H), 2.76 (t, J = 9.6 Hz, 1H), 2.57 (dd, J = 11.6, 1.2 Hz, 1H), 2.40-2.30 (m, 1H), 2.19 −2.05 (m, 2H), 1.76–1.73 (m, 1H), 1.64–1.58 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H); MS m/z: 437 [M+H] + .

실시예 39: 5-아미노-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 39: 5-amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)p Peridin-3-ol

Figure pct00109
Figure pct00109

단계 1: 5-(tert-부톡시카르보닐아미노)-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올의 합성Step 1: 5-(tert-butoxycarbonylamino)-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- Synthesis of yl]amino}phenyl)piperidin-3-ol

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 tert-부틸 (3-히드록시피페리딘-5-일)카르바메이트를 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 2-메틸피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 5-(tert-부톡시카르보닐아미노)-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올을 수득하였다.In step 1 of Example 14, tert -butyl (3-hydroxypiperidin-5-yl)carbamate was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, 2,3- 5-( tert -butoxycarbonylamino)-1-(4-{[4-(2- Methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3-ol was obtained.

단계 2: 5-아미노-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올(실시예 39의 화합물)의 합성Step 2: 5-Amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)piperi Synthesis of din-3-ol (compound of Example 39)

상기 단계 1에서 수득된 화합물을 실시예 38의 단계 2와 동일한 방법으로 반응시켜 5-아미노-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올(실시예 39의 화합물)을 담황색 고체로 수득하였다. 1H NMR (400 MHz, DMSO-d6); δ 9.40 (brs, 1H), 8.27 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 6.91-6.87 (m, 2H), 3.74-3.67 (m, 2H), 3.62-3.40 (m, 4H), 3.21 - 3.06 (m, 2H), 2.82 (m, 1H), 2.67 (m, 1H), 2.31-2.29 (m, 1H), 2.09-2.04 (m, 1H), 1.88-1.68 (m, 1H), 1.57-1.40 (m, 2H), 1.07 (d, J = 6.4 Hz, 3H); MS m/z: 437 [M+H]+.The compound obtained in step 1 was reacted in the same manner as in step 2 of Example 38 to obtain 5-amino-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(tri) Obtained fluoromethyl)pyrimidin-2-yl]amino}phenyl)piperidin-3-ol (compound of Example 39) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ); δ 9.40 (brs, 1H), 8.27 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 6.91-6.87 (m, 2H), 3.74-3.67 (m, 2H), 3.62-3.40 (m , 4H), 3.21 - 3.06 (m, 2H), 2.82 (m, 1H), 2.67 (m, 1H), 2.31-2.29 (m, 1H), 2.09-2.04 (m, 1H), 1.88-1.68 (m , 1H), 1.57–1.40 (m, 2H), 1.07 (d, J = 6.4 Hz, 3H); MS m/z: 437 [M+H] + .

실시예 40: 4-(2-{[4-(4-아미노-3-히드록시피페리딘-1-일)페닐]아미노}-5-(트리플루오로메틸)피리미딘-4-일)모르폴린-2-카르보니트릴Example 40: 4-(2-{[4-(4-amino-3-hydroxypiperidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl) Morpholine-2-carbonitrile

Figure pct00110
Figure pct00110

단계 1: tert-부틸 (1-(4-((4-(2-시아노모르폴리노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)페닐)-3-히드록시피페리딘-4-일)카르바메이트의 합성Step 1: tert-Butyl (1-(4-((4-(2-cyanomorpholino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-3-hydroxy Synthesis of cypiperidin-4-yl)carbamate

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 tert-부틸 (3-히드록시피페리딘-4-일)카르바메이트를 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 모르폴린-2-카르보니트릴을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 tert-부틸 (1-(4-((4-(2-시아노모르폴리노)-5-(트리플루오로메틸)피리미딘-2-일)아미노)페닐)-3-히드록시피페리딘-4-일)카르바메이트를 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.34 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.90 (s, 1H), 4.04-3.98 (m, 2H), 3.85-3.83 (m, 2H), 3.73-3.70(m, 2H), 3.57-3.54 (m, 2H), 3.48-3.32 (m, 3H), 2.76-2.70 (m, 1H), 2.58 (dd, J = 10.8 Hz, 1H), 2.03-2.01 (m, 1H), 1.65-1.58 (m, 1H), 1.46 (s, 9H).In step 1 of Example 14, tert -butyl (3-hydroxypiperidin-4-yl)carbamate was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, 2,3- tert -butyl (1-(4-((4-(2-cyanomorpholino)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate was obtained. 1 H NMR (400 MHz, CD 3 OD); δ 8.34 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.90 (s, 1H), 4.04–3.98 (m, 2H), 3.85– 3.83 (m, 2H), 3.73-3.70 (m, 2H), 3.57-3.54 (m, 2H), 3.48-3.32 (m, 3H), 2.76-2.70 (m, 1H), 2.58 (dd, J = 10.8 Hz, 1H), 2.03–2.01 (m, 1H), 1.65–1.58 (m, 1H), 1.46 (s, 9H).

단계 2: 4-(2-{[4-(4-아미노-3-히드록시피페리딘-1-일)페닐]아미노}-5-(트리플루오로메틸)피리미딘-4-일)모르폴린-2-카르보니트릴(실시예 40의 화합물)의 합성Step 2: 4-(2-{[4-(4-amino-3-hydroxypiperidin-1-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)mor Synthesis of Foline-2-carbonitrile (Compound of Example 40)

상기 단계 1에서 수득된 화합물을 실시예 38의 단계 2와 동일한 방법으로 반응시켜 4-(2-{[4-(4-아미노-3-히드록시피페리딘-1-일)페닐]아미노}-5-(트리플루오로메틸)피리미딘-4-일)모르폴린-2-카르보니트릴(실시예 40의 화합물)을 황색 고체로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.33 (s, 1H), 7.45 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.89 (m, 1H), 4.02-3.95 (m, 2H), 3.85-3.73 (m, 4H), 3.70-3.58(m, 2H), 3.44-3.41 (m, 1H), 2.85 (m, 1H), 2.74 (m, 1H), 2.55 (dd, J = 11.2 Hz, 1H), 2.03-2.02 (m, 1H), 1.72-1.68 (m, 1H); MS m/z: 464 [M+H]+.The compound obtained in step 1 was reacted in the same manner as in step 2 of Example 38 to obtain 4-(2-{[4-(4-amino-3-hydroxypiperidin-1-yl)phenyl]amino} Obtained -5-(trifluoromethyl)pyrimidin-4-yl)morpholine-2-carbonitrile (compound of Example 40) as a yellow solid. 1 H NMR (400 MHz, CD 3 OD); δ 8.33 (s, 1H), 7.45 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.89 (m, 1H), 4.02–3.95 (m, 2H), 3.85– 3.73 (m, 4H), 3.70-3.58 (m, 2H), 3.44-3.41 (m, 1H), 2.85 (m, 1H), 2.74 (m, 1H), 2.55 (dd, J = 11.2 Hz, 1H) , 2.03-2.02 (m, 1H), 1.72-1.68 (m, 1H); MS m/z: 464 [M+H] + .

실시예 41: (3R,4R)-4-플루오로-1-(4-{[4-(2-메틸피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 41: (3R,4R)-4-fluoro-1-(4-{[4-(2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2- yl]amino}phenyl)piperidin-3-ol

Figure pct00111
Figure pct00111

실시예 14의 단계 1에서 3-히드록시피페리딘 대신에 (3R,4R)-4-플루오로피페리딘-3-올을 사용하고, 실시예 14의 단계 4에서 2,3-디메틸피롤리딘 염산염 대신에 2-메틸피롤리딘을 사용한 것을 제외하고, 실시예 14와 동일한 방법으로 실시예 41의 화합물을 백색 분말로 수득하였다. 1H NMR (400 MHz, CD3OD); δ 8.18 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.50-4.42 (m, 0.5H), 4.36-4.28 (m, 0.5H), 3.83-3.76 (m, 3H), 3.69-3.58 (m, 2H), 3.52-3.49 (m, 1H), 3.19 (t, J = 9.6 Hz, 1H), 2.83 (t, J = 11.6 Hz, 1H), 2.69 (t, J = 11.2 Hz, 1H), 2.34-2.31(m, 1H), 2.17-2.10 (m, 2H), 1.87-1.82 (m, 1H), 1.61-1.56 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H); MS m/z: 440 [M+H]+.In step 1 of Example 14, (3R,4R)-4-fluoropiperidin-3-ol was used instead of 3-hydroxypiperidine, and in step 4 of Example 14, 2,3-dimethylpiperidine was used. The compound of Example 41 was obtained as a white powder in the same manner as in Example 14, except that 2-methylpyrrolidine was used instead of rolidine hydrochloride. 1 H NMR (400 MHz, CD 3 OD); δ 8.18 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.50–4.42 (m, 0.5H), 4.36–4.28 (m, 0.5H) ), 3.83-3.76 (m, 3H), 3.69-3.58 (m, 2H), 3.52-3.49 (m, 1H), 3.19 (t, J = 9.6 Hz, 1H), 2.83 (t, J = 11.6 Hz, 1H), 2.69 (t, J = 11.2 Hz, 1H), 2.34-2.31 (m, 1H), 2.17-2.10 (m, 2H), 1.87-1.82 (m, 1H), 1.61-1.56 (m, 1H) , 1.12 (d, J = 6.4 Hz, 3H); MS m/z: 440 [M+H] + .

실시예 42 및 43: (3S,4R)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)-4-메틸피롤리딘-3-올(실시예 42의 화합물) 및 (3R,4S)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)-4-메틸피롤리딘-3-올(실시예 43의 화합물)Examples 42 and 43: (3S,4R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidine-2 -yl]amino}phenyl)-4-methylpyrrolidin-3-ol (compound of Example 42) and (3R,4S)-1-(4-{[4-(3,3-difluoropy) Rolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-4-methylpyrrolidin-3-ol (Compound of Example 43)

Figure pct00112
Figure pct00113
Figure pct00112
Figure pct00113

제조예 1의 화합물 (150 mg, 521.53 umol, 1당량) 및 제조예 2의 화합물 (120.32 mg, 625.83 umol, 1.2당량)을 IPA (2 mL) 중에 혼합하고, DIPEA (134.81 mg, 1.04 mmol, 181.68 uL, 2당량)을 첨가하여 90℃에서 12시간 동안 교반하였다. TLC (석유에테르 : 에틸아세테이트 = 1:1, 원하는 생성물 Rf = 0.6)는 반응이 완료되었음을 나타내었다. LCMS(t=1.095)는 원하는 생성물을 나타내었다. 혼합물을 20℃로 냉각하고 40℃에서 감압 농축시켰다. 잔사를 에틸아세테이트 (w/w = 1/1) (20 mL)에 붓고, 물 (30 mL)로 세척한 후 40℃에서 감압 농축시켰다. 잔사를 prep-TLC (석유에테르/에틸아세테이트 = 1/1)로 정제하여 1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)-4-메틸피롤리딘-3-올 (87 mg, 37.6% 수율)를 황색 고체로 수득하였다. 1H-NMR (CDCl3, 400 MHz) δ (ppm): 8.30 (s, 1 H), 7.30-7.41 (m, 2 H), 6.93-7.10 (m, 1 H), 6.46-6.59 (m, 2 H), 4.06-4.20 (m, 1 H), 3.85-4.03 (m, 4 H), 3.57-3.68 (m, 2 H), 3.25 (dd, J = 10.2, 4.0 Hz, 1 H), 2.98 (dd, J = 8.8, 5.2 Hz, 1 H), 2.25-2.50 (m, 3 H), 1.71-1.80 (m, 1 H), 1.06-1.17 (m, 3 H); LCMS: Rt = 1.095분, MS m/z: 444.1 [M+H]+.The compound of Preparation Example 1 (150 mg, 521.53 umol, 1 equivalent) and the compound of Preparation Example 2 (120.32 mg, 625.83 umol, 1.2 equivalent) were mixed in IPA (2 mL), and DIPEA (134.81 mg, 1.04 mmol, 181.68 uL, 2 equivalents) was added and stirred at 90° C. for 12 hours. TLC (petroleum ether : ethyl acetate = 1:1, desired product Rf = 0.6) showed the reaction to be complete. LCMS (t=1.095) showed the desired product. The mixture was cooled to 20°C and concentrated under reduced pressure at 40°C. The residue was poured into ethyl acetate (w/w = 1/1) (20 mL), washed with water (30 mL), and then concentrated under reduced pressure at 40°C. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/1) to obtain 1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoro Obtained romethyl)pyrimidin-2-yl]amino}phenyl)-4-methylpyrrolidin-3-ol (87 mg, 37.6% yield) as a yellow solid. 1 H-NMR (CDCl 3 , 400 MHz) δ (ppm): 8.30 (s, 1 H), 7.30-7.41 (m, 2 H), 6.93-7.10 (m, 1 H), 6.46-6.59 (m, 2 H), 4.06-4.20 (m, 1 H), 3.85-4.03 (m, 4 H), 3.57-3.68 (m, 2 H), 3.25 (dd, J = 10.2, 4.0 Hz, 1 H), 2.98 (dd, J = 8.8, 5.2 Hz, 1 H), 2.25–2.50 (m, 3 H), 1.71–1.80 (m, 1 H), 1.06–1.17 (m, 3 H); LCMS: Rt = 1.095 min, MS m/z: 444.1 [M+H] + .

수득된 화합물을 prep-SFC (INC_ETOH (DEA) _5_40_2,8ML_8MIN.M)에 적용하였다. 두 개의 거울상 이성질체를 각각 감압 농축시킨 다음 동결 건조하여 (3S,4R)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)-4-메틸피롤리딘-3-올(실시예 42의 화합물) (23 mg, 51.87 umol, 27.06% 수율) 및 (3R,4S)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)-4-메틸피롤리딘-3-올(실시예 43의 화합물) (27 mg,　60.89 umol, 31.76% 수율, Rt = 3.005분)을 각각 황색 고체로 수득하였다(이들의 절대 구조는 임의로 지정됨).The obtained compound was applied to prep-SFC (INC_ETOH (DEA) _5_40_2,8ML_8MIN.M). Each of the two enantiomers was concentrated under reduced pressure and then lyophilized to (3S,4R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluorocarbon). Romethyl)pyrimidin-2-yl]amino}phenyl)-4-methylpyrrolidin-3-ol (compound of Example 42) (23 mg, 51.87 umol, 27.06% yield) and (3R,4S)- 1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-4-methylpyridine Rolidin-3-ol (compound of Example 43) (27 mg, 60.89 umol, 31.76% yield, Rt = 3.005 min) were each obtained as a yellow solid (their absolute structures are arbitrarily assigned).

(3S,4R)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)-4-메틸피롤리딘-3-올(실시예 42의 화합물)(3S,4R)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl )-4-methylpyrrolidin-3-ol (compound of Example 42)

1H NMR (400 MHz, CDCl3)δ ppm 8.30 (s, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 6.98 (br s, 1 H), 6.53 (d, J = 8.4 Hz, 2 H), 4.12-4.10 (m, 1 H), 4.01-3.88 (m, 4 H), 3.68-3.58 (m, 2 H), 3.25-3.23 (m, 1 H), 3.09-2.93 (m, 1 H), 2.45-2.30 (m, 3 H), 1.11 (d, J = 7.2 Hz, 3 H); LCMS: RT = 1.092분, MS m/z = 444.1 [M+H]+; HPLC: 순도 = 97.6% (area%); 키랄 SFC: ee% = 100% (area%). 1 H NMR (400 MHz , CDCl 3 )δ ppm 8.30 (s, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 6.98 (br s, 1 H), 6.53 (d, J = 8.4 Hz , 2 H), 4.12-4.10 (m, 1 H), 4.01-3.88 (m, 4 H), 3.68-3.58 (m, 2 H), 3.25-3.23 (m, 1 H), 3.09-2.93 (m , 1 H), 2.45–2.30 (m, 3 H), 1.11 (d, J = 7.2 Hz, 3 H); LCMS: RT = 1.092 min, MS m/z = 444.1 [M+H] + ; HPLC: purity = 97.6% (area%); Chiral SFC: ee% = 100% (area%).

(3R,4S)-1-(4-{[4-(3,3-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일]아미노}페닐)-4-메틸피롤리딘-3-올(실시예 43의 화합물)(3R,4S)-1-(4-{[4-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl )-4-methylpyrrolidin-3-ol (compound of Example 43)

1H NMR (400 MHz, CDCl3) δ ppm 8.31 (s, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 6.96 (br s, 1 H), 6.54 (d, J = 8.4 Hz, 2 H), 4.12-4.10 (m, 1 H), 4.01-3.88 (m, 4 H), 3.68-3.58 (m, 2 H), 3.27-3.23 (m, 1 H), 3.00-2.96 (m, 1 H), 2.44-2.30 (m, 3 H), 1.11 (d, J = 7.2 Hz, 3 H); LCMS: RT = 1.095분, MS m/z = 444.2 [M+H]+; HPLC: 순도 = 96.7% (area%); 키랄 SFC: ee% = 97.2% (area%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.31 (s, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 6.96 (br s, 1 H), 6.54 (d, J = 8.4 Hz , 2 H), 4.12-4.10 (m, 1 H), 4.01-3.88 (m, 4 H), 3.68-3.58 (m, 2 H), 3.27-3.23 (m, 1 H), 3.00-2.96 (m , 1 H), 2.44–2.30 (m, 3 H), 1.11 (d, J = 7.2 Hz, 3 H); LCMS: RT = 1.095 min, MS m/z = 444.2 [M+H] + ; HPLC: purity = 96.7% (area%); Chiral SFC: ee% = 97.2% (area%).

실시예 44: N-[4-(3-클로로피페리딘-1-일)페닐]-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-아민Example 44: N-[4-(3-chloropiperidin-1-yl)phenyl]-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5 -(trifluoromethyl)pyrimidin-2-amine

Figure pct00114
Figure pct00114

실시예 44의 화합물을 하기 반응식 3에 따라서 합성하였다.The compound of Example 44 was synthesized according to Scheme 3 below.

[반응식 3][Scheme 3]

Figure pct00115
Figure pct00115

단계 1: 3-클로로-1-(4-니트로페닐)피페리딘의 합성Step 1: Synthesis of 3-chloro-1-(4-nitrophenyl)piperidine

ACN (3 mL) 중에 4-플루오로니트로벤젠 (100 mg, 0.70 mmol, 1.00당량) 및 3-클로로피페리딘 염산염 (99 mg, 0.63 mmol, 0.90당량)을 교반 혼합하고, DIEA (366 mg, 2.83 mmol, 4.00당량)을 첨가하였다. 생성된 혼합물을 100℃에서 16시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 혼합물을 PE/EtOAc (10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 3-클로로-1-(4-니트로페닐)피페리딘 (65 mg, 31.63%)을 황색 고체로 수득하였다. MS m/z: 241/243 [M+H]+.Stir-mix 4-fluoronitrobenzene (100 mg, 0.70 mmol, 1.00 equiv) and 3-chloropiperidine hydrochloride (99 mg, 0.63 mmol, 0.90 equiv) in ACN (3 mL), DIEA (366 mg, 2.83 mmol, 4.00 equiv) was added. The resulting mixture was stirred at 100° C. for 16 hours, and the mixture was cooled to room temperature. The mixture was purified by silica gel column chromatography, eluting with PE/EtOAc (10:1) to give 3-chloro-1-(4-nitrophenyl)piperidine (65 mg, 31.63%) as a yellow solid. MS m/z: 241/243 [M+H] + .

단계 2: 4-(3-클로로피페리딘-1-일)아닐린의 합성Step 2: Synthesis of 4-(3-chloropiperidin-1-yl)aniline

상기 단계 1에서 수득된 화합물 (65 mg, 0.27 mmol, 1.00당량) 및 Pd/C (10 mg, 10%)를 MeOH (5 mL) 중에 교반 혼합하고, 수소 대기하에 25℃에서 40분 동안 교반하였다. 생성된 혼합물을 여과하고, 필터 케이크를 MeOH (3×10 mL)로 세척하였다. 여액을 감압 농축시키고, 다음 단계에서 직접 사용하였다. MS m/z: 211/213 [M+H]+.The compound obtained in step 1 above (65 mg, 0.27 mmol, 1.00 equiv.) and Pd/C (10 mg, 10%) were stirred and mixed in MeOH (5 mL) and stirred at 25° C. for 40 min under a hydrogen atmosphere. . The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure and used directly in the next step. MS m/z: 211/213 [M+H] + .

단계 3: N-[4-(3-클로로피페리딘-1-일)페닐]-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-아민(실시예 44의 화합물)의 합성Step 3: N-[4-(3-chloropiperidin-1-yl)phenyl]-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5- Synthesis of (trifluoromethyl)pyrimidin-2-amine (Compound of Example 44)

제조예 3의 화합물 (54 mg, 0.19 mmol, 1.00당량)을 n-BuOH (2 mL) 중에 교반 혼합하고, 상기 단계 2에서 수득된 화합물 (40 mg, 0.19 mmol, 1.00당량) 및 HCl (1 방울)을 첨가하였다. 생성된 혼합물을 80℃에서 1시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 혼합물을 CH2Cl2/MeOH (10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하였다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Shield RP18 OBD 컬럼, 30×150 mm, 5 um; 이동상, 물 (10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN (55% Phase B, 10분에 68%까지); 검출기, UV 254 nm. 수집된 분획을 동결건조하여 N-[4-(3-클로로피페리딘-1-일)페닐]-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-아민 (실시예 44의 화합물; 9 mg, 10.21%)을 백색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.58 (s, 1H), 8.36 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.56-5.50 (m, 1H), 5.50-5.43 (m, 1H), 4.28-4.22 (m, 1H), 4.04-3.84 (m, 4H), 3.69-3.65 (m, 1H), 3.35-3.34 (m, 1H), 2.99-2.93 (m, 1H), 2.92-2.83 (m, 1H), 2.18-2.07 (m, 1H), 1.86-1.81 (m, 1H), 1.73-1.61 (m, 2H); MS m/z: 462/464 [M+H]+.The compound of Preparation Example 3 (54 mg, 0.19 mmol, 1.00 equiv) was stirred and mixed in n-BuOH (2 mL), and the compound obtained in Step 2 (40 mg, 0.19 mmol, 1.00 equiv) and HCl (1 drop) were mixed. ) was added. The resulting mixture was stirred at 80° C. for 1 hour, and the mixture was cooled to room temperature. The mixture was purified by silica gel column chromatography, eluting with CH 2 Cl 2 /MeOH (10:1). The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 30×150 mm, 5 um; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (55% Phase B, up to 68% in 10 min); Detector, UV 254 nm. The collected fractions were lyophilized and N-[4-(3-chloropiperidin-1-yl)phenyl]-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl Obtained ]-5-(trifluoromethyl)pyrimidin-2-amine (compound of Example 44; 9 mg, 10.21%) as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.58 (s, 1H), 8.36 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.56-5.50 (m, 1H), 5.50-5.43 (m, 1H), 4.28-4.22 (m, 1H), 4.04-3.84 (m, 4H), 3.69-3.65 (m, 1H) ( m, 2H); MS m/z: 462/464 [M+H] + .

실시예 45: 4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-N-[4-(3-플루오로피페리딘-1-일)페닐]-5-(트리플루오로메틸)피리미딘-2-아민Example 45: 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-N-[4-(3-fluoropiperidin-1-yl)phenyl]- 5-(trifluoromethyl)pyrimidin-2-amine

Figure pct00116
Figure pct00116

실시예 44의 단계 1에서 3-클로로피페리딘 염산염 대신에 3-플루오로피페리딘 염산염을 사용한 것을 제외하고, 실시예 44와 동일한 방법으로 실시예 45의 화합물을 백색 고체 (5.6 mg, 6.01%)로 수득하였다. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.57 (s, 1H), 8.36 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 9.2 Hz, 2H), 5.56-5.43 (m, 2H), 4.86-4.71 (m, 1H), 4.04-3.84 (m, 4H), 3.39-3.36 (m, 1H), 3.17-3.01 (m, 3H), 1.93-1.81 (m, 2H), 1.80-1.56 (m, 2H); MS m/z: 446 [M+H]+.The compound of Example 45 was obtained as a white solid (5.6 mg, 6.01 %) was obtained. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.57 (s, 1H), 8.36 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 9.2 Hz, 2H), 5.56-5.43 (m, 2H), 4.86-4.71 (m, 1H), 4.04-3.84 (m, 4H), 3.39-3.36 (m, 1H), 3.17-3.01 (m, 3H), 1.93-1.81 (m, 2H), 1.80-1.56 (m, 2H); MS m/z: 446 [M+H] + .

실시예 46: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(트리플루오로메틸)피리미딘-2-일}아미노)페닐]피페리딘-3-카르보니트릴Example 46: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl }amino)phenyl]piperidine-3-carbonitrile

Figure pct00117
Figure pct00117

실시예 44의 단계 1에서 3-클로로피페리딘 염산염 대신에 피페리딘-3-카르보니트릴 염산염을 사용한 것을 제외하고, 실시예 44와 동일한 방법으로 실시예 46의 화합물을 백색 고체 (7.8 mg, 8.23%)로 수득하였다. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.59 (s, 1H), 8.36 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.56-5.50 (m, 1H), 5.50-5.43 (m, 1H), 4.04-3.85 (m, 4H), 3.30-3.24 (m, 2H), 3.16-3.11 (m, 2H), 3.05-3.00 (m, 1H), 1.87-1.72 (m, 3H), 1.71-1.63 (m, 1H); MS m/z: 453 [M+H]+.The compound of Example 46 was prepared as a white solid (7.8 mg, 8.23%). 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.59 (s, 1H), 8.36 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.56-5.50 (m, 1H), 5.50-5.43 (m, 1H), 4.04-3.85 (m, 4H), 3.30-3.24 (m, 2H), 3.16-3.11 (m, 2H), 3.05-3.00 (m, 1H), 1.87-1.72 (m, 3H), 1.71-1.63 (m, 1H); MS m/z: 453 [M+H] + .

실시예 47: 4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-N-{4-[3-(모르폴린-4-일)아제티딘-1-일]페닐}-5-(트리플루오로메틸)피리미딘-2-아민Example 47: 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-N-{4-[3-(morpholin-4-yl)azetidin-1- yl]phenyl}-5-(trifluoromethyl)pyrimidin-2-amine

Figure pct00118
Figure pct00118

실시예 44의 단계 1에서 3-클로로피페리딘 염산염 대신에 4-(아제티딘-3-일)모르폴린 염산염을 사용한 것을 제외하고, 실시예 44와 동일한 방법으로 실시예 47의 화합물을 황백색 고체 (12.3 mg, 12%)로 수득하였다. 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 9.47 (s, 1H), 8.33 (s, 1H), 7.47 (d, J = 9.0 Hz, 2H), 6.41 (d, J = 9.0 Hz, 2H), 5.58-5.56 (m, 1H), 5.42-5.40 (m, 1H), 4.05-3.85 (m, 6H), 3.60-3.52 (m, 6H), 3.26-3.18 (m, 1H), 2.32 (s, 4H); MS m/z: 485 [M+H]+.The compound of Example 47 was obtained as a yellowish-white solid in the same manner as in Example 44, except that 4-(azetidin-3-yl)morpholine hydrochloride was used instead of 3-chloropiperidine hydrochloride in step 1 of Example 44. (12.3 mg, 12%). 1 H NMR (DMSO-d 6 , 300 MHz) δ (ppm): 9.47 (s, 1H), 8.33 (s, 1H), 7.47 (d, J = 9.0 Hz, 2H), 6.41 (d, J = 9.0 Hz, 2H), 5.58-5.56 (m, 1H), 5.42-5.40 (m, 1H), 4.05-3.85 (m, 6H), 3.60-3.52 (m, 6H), 3.26-3.18 (m, 1H), 2.32 (s, 4H); MS m/z: 485 [M+H] + .

실시예 48: 1-(4-{[5-(2-클로로에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 48: 1-(4-{[5-(2-chloroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl ]amino}phenyl)piperidin-3-ol

Figure pct00119
Figure pct00119

실시예 48의 화합물을 하기 반응식 4에 따라서 합성하였다.The compound of Example 48 was synthesized according to Scheme 4 below.

[반응식 4][Scheme 4]

Figure pct00120
Figure pct00120

단계 1: (2,4-디옥소-3,5-디하이드로피리미딘-5-일)아세트산의 합성Step 1: Synthesis of (2,4-dioxo-3,5-dihydropyrimidin-5-yl)acetic acid

AcOH (500 mL) 중에 우라실 (100 g, 892.15 mmol, 1.00당량)을 교반 혼합하고, 옥소(포스파닐)보란 (53 g, 892.15 mmol, 1.00당량)을 첨가하였다. 생성된 혼합물을 질소 대기하에 100℃에서 48시간 동안 교반하였다. 혼합물을 실온으로 냉각하고, 반응을 물 (500 mL)로 ??칭(quench)시켰다. 생성된 혼합물을 여과하고, 여액을 감압 농축시켜서 (2,4-디옥소-3,5-디하이드로피리미딘-5-일)아세트산 (10g, 미정제)을 황백색 고체로 수득하였다. MS m/z: 171 [M+H]+, 169 [M-H]-.Uracil (100 g, 892.15 mmol, 1.00 equiv) in AcOH (500 mL) was stirred and mixed, and oxo(phosphanyl)borane (53 g, 892.15 mmol, 1.00 equiv) was added. The resulting mixture was stirred at 100° C. for 48 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and the reaction was quenched with water (500 mL). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give (2,4-dioxo-3,5-dihydropyrimidin-5-yl)acetic acid (10 g, crude) as an off-white solid. MS m/z: 171 [M+H] + , 169 [MH] - .

단계 2: 에틸 2-(2,4-디옥소-3,5-디하이드로피리미딘-5-일)아세테이트의 합성Step 2: Synthesis of ethyl 2-(2,4-dioxo-3,5-dihydropyrimidin-5-yl)acetate

단계 1에서 수득된 화합물 (10g, 58.78 mmol, 1.00당량)을 EtOH (150 mL) 중에 교반 혼합하고, H2SO4 (15 mL, 281.40 mmol, 4.79당량)를 0℃에서 적가하였다. 생성된 혼합물을 100℃에서 16시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 생성된 혼합물을 진공 하에 농축시키고, 혼합물을 NaHCO3로 중화하였다. 잔사를 PE/EtOAc (1:10)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 에틸 2-(2,4-디옥소-3,5-디하이드로피리미딘-5-일)아세테이트 (2.0g, 15.45%)을 황백색 고체로 수득하였다. MS m/z: 199 [M+H]+.The compound obtained in step 1 (10 g, 58.78 mmol, 1.00 equiv) was stirred mixed in EtOH (150 mL) and H 2 SO 4 (15 mL, 281.40 mmol, 4.79 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 100° C. for 16 hours, and the mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum and the mixture was neutralized with NaHCO 3 . The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:10) to give ethyl 2-(2,4-dioxo-3,5-dihydropyrimidin-5-yl)acetate (2.0 g, 15.45 %) was obtained as an off-white solid. MS m/z: 199 [M+H] + .

단계 3: 에틸 2-(2,4-디클로로피리미딘-5-일)아세테이트의 합성Step 3: Synthesis of ethyl 2-(2,4-dichloropyrimidin-5-yl)acetate

단계 2에서 수득된 화합물 (2.00g, 10.09 mmol, 1.00당량)을 POCl3 (20 mL) 중에 교반 혼합하고, DIEA (3.91g, 30.25 mmol, 3.00당량)를 0℃에서 적가하였다. 생성된 혼합물을 질소 대기하에 100℃에서 16시간 동안 교반하였다. 혼합물을 실온으로 냉각하고, 반응을 물/얼음 (100 mL)로 ??칭시켰다. 생성된 혼합물을 EtOEt (2×100 mL)로 추출하고, 유기층을 모아서 무수 Na2SO4 상에서 건조시켰다. 여과 후 여액을 감압 농축시키고, 잔사를 PE/EtOAc (1:3)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 에틸 2-(2,4-디클로로피리미딘-5-일)아세테이트 (1.1 g, 44.05%)를 연황색(light yellow) 오일로 수득하였다. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 8.82 (s, 1H), 4.18-4.11 (m, 2H), 3.91 (s, 2H), 1.24-1.17 (m, 3H); MS m/z: 235/237/239 [M+H]+.The compound obtained in step 2 (2.00 g, 10.09 mmol, 1.00 equiv) was stirred mixed in POCl 3 (20 mL) and DIEA (3.91 g, 30.25 mmol, 3.00 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 100° C. for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and the reaction was quenched with water/ice (100 mL). The resulting mixture was extracted with EtOEt (2×100 mL) and the combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:3) and purified by silica gel column chromatography to obtain ethyl 2-(2,4-dichloropyrimidin-5-yl)acetate (1.1 g, 44.05 %) was obtained as a light yellow oil. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.82 (s, 1H), 4.18-4.11 (m, 2H), 3.91 (s, 2H), 1.24-1.17 (m, 3H); MS m/z: 235/237/239 [M+H] + .

단계 4: 에틸 2-[2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-5-일]아세테이트의 합성Step 4: Synthesis of ethyl 2-[2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-5-yl]acetate

단계 3에서 수득된 화합물 (800 mg, 3.40 mmol, 1.00당량) 및 (3S,4S)-3,4-디플루오로피롤리딘 염산염 (488 mg, 3.40 mmol, 1.00당량)을 ACN (20 mL) 중에 교반 혼합하고, DIEA (1.32 g, 10.20 mmol, 3.00당량)를 첨가하였다. 생성된 혼합물을 질소 대기하에 80℃에서 2시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 생성된 혼합물을 진공 하에 농축시키고, 잔사를 PE/EtOAc (1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 에틸 2-[2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-5-일]아세테이트 (850 mg, 75.16%)를 백색 고체로 수득하였다. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 8.02 (s, 1H), 5.55-5.52 (m, 1H), 5.38-5.36 (m, 1H), 4.15-4.10 (m, 2H), 4.08-3.84 (m, 6H), 1.20-1.16 (m, 3H); MS m/z: 306/308 [M+H]+.The compound obtained in step 3 (800 mg, 3.40 mmol, 1.00 equiv) and (3S,4S)-3,4-difluoropyrrolidine hydrochloride (488 mg, 3.40 mmol, 1.00 equiv) were added to ACN (20 mL). After mixing with stirring, DIEA (1.32 g, 10.20 mmol, 3.00 equiv) was added. The resulting mixture was stirred at 80° C. for 2 hours under a nitrogen atmosphere, and the mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give ethyl 2-[2-chloro-4-[(3S,4S)-3,4- Obtained difluoropyrrolidin-1-yl]pyrimidin-5-yl]acetate (850 mg, 75.16%) as a white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.02 (s, 1H), 5.55-5.52 (m, 1H), 5.38-5.36 (m, 1H), 4.15-4.10 (m, 2H) ), 4.08-3.84 (m, 6H), 1.20-1.16 (m, 3H); MS m/z: 306/308 [M+H] + .

단계 5: 에틸 2-[2-([4-[3-(벤질옥시)피페리딘-1-일]페닐]아미노)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-5-일]아세테이트의 합성Step 5: Ethyl 2-[2-([4-[3-(benzyloxy)piperidin-1-yl]phenyl]amino)-4-[(3S,4S)-3,4-difluoropy Synthesis of rolidin-1-yl]pyrimidin-5-yl]acetate

단계 4에서 수득된 화합물 (850 mg, 2.78 mmol, 1.00당량) 및 제조예 4의 화합물 (1.18 g, 4.17 mmol, 1.50당량)을 n-BuOH (20 mL) 중에 교반 혼합하고, 농염산 (10 방울)을 첨가하였다. 생성된 혼합물을 질소 대기하에 80℃에서 6시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 조 생성물을 PE/EtOAc (1:10)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 에틸 2-[2-([4-[3-(벤질옥시)피페리딘-1-일]페닐]아미노)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-5-일]아세테이트 (800 mg, 44.33%)를 황백색 고체로 수득하였다. MS m/z: 552 [M+H]+.The compound obtained in Step 4 (850 mg, 2.78 mmol, 1.00 equiv) and the compound of Preparation 4 (1.18 g, 4.17 mmol, 1.50 equiv) were stirred and mixed in n-BuOH (20 mL), concentrated hydrochloric acid (10 drops) ) was added. The resulting mixture was stirred at 80° C. for 6 hours under a nitrogen atmosphere, and the mixture was cooled to room temperature. The crude product was purified by silica gel column chromatography eluting with PE/EtOAc (1:10) to yield ethyl 2-[2-([4-[3-(benzyloxy)piperidin-1-yl]phenyl]amino) Obtained -4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-5-yl]acetate (800 mg, 44.33%) as an off-white solid. MS m/z: 552 [M+H] + .

단계 6: 2-[2-([4-[3-(벤질옥시)피페리딘-1-일]페닐]아미노)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-5-일]에탄올의 합성Step 6: 2-[2-([4-[3-(benzyloxy)piperidin-1-yl]phenyl]amino)-4-[(3S,4S)-3,4-difluoropyrroly Synthesis of din-1-yl] pyrimidin-5-yl] ethanol

단계 5에서 수득된 화합물 (700 mg, 1.269 mmol, 1.00당량)을 THF (20 mL) 중에 교반 혼합하고, 디이소부틸알루미늄 하이드라이드(DIBAL_H) (THF 중 1M, 5.08 mL, 5.08 mmol, 4.00당량)을 질소 대기하에 0℃에서 적가하였다. 생성된 혼합물을 질소 대기하에 0℃에서 3시간 동안 교반하였다. 반응을 0℃에서 HCl (1M) (5 mL)로 ??칭시켰다. 생성된 혼합물을 감압 농축시키고, 잔사를 CH2Cl2/MeOH (10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2-[2-([4-[3-(벤질옥시)피페리딘-1-일]페닐]아미노)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-5-일]에탄올 (400 mg, 55.67%)을 황백색 고체로 수득하였다. MS m/z: 510 [M+H]+.The compound obtained in Step 5 (700 mg, 1.269 mmol, 1.00 equiv) was stirred mixed in THF (20 mL) and diisobutylaluminum hydride (DIBAL_H) (1M in THF, 5.08 mL, 5.08 mmol, 4.00 equiv). was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 3 hours under a nitrogen atmosphere. The reaction was quenched with HCl (1M) (5 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with CH 2 Cl 2 /MeOH (10:1) to give 2-[2-([4-[3-(benzyloxy)piperidine -1-yl]phenyl]amino)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-5-yl]ethanol (400 mg, 55.67%) Obtained as an off-white solid. MS m/z: 510 [M+H] + .

단계 7: N-[4-[3-(벤질옥시)피페리딘-1-일]페닐]-5-(2-클로로에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-아민의 합성Step 7: N-[4-[3-(benzyloxy)piperidin-1-yl]phenyl]-5-(2-chloroethyl)-4-[(3S,4S)-3,4-difluoro Synthesis of ropyrrolidin-1-yl] pyrimidin-2-amine

단계 6에서 수득된 화합물 (80 mg, 0.15 mmol, 1.00당량)을 DCM (5.00 mL) 중에 교반 혼합하고, SOCl2 (186 mg, 1.57 mmol, 10.00당량)을 질소 대기하에 0℃에서 적가하였다. 생성된 혼합물을 질소 대기하에 25℃에서 16시간 동안 교반하였다. 생성된 혼합물을 진공 하에 농축시키고, 잔사를 CH2Cl2/MeOH (10:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 N-[4-[3-(벤질옥시)피페리딘-1-일]페닐]-5-(2-클로로에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-아민 (60 mg, 65.14%)을 황백색 고체로 수득하였다. MS m/z: 528/530 [M+H]+.The compound obtained in step 6 (80 mg, 0.15 mmol, 1.00 equiv) was stirred mixed in DCM (5.00 mL) and SOCl 2 (186 mg, 1.57 mmol, 10.00 equiv) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with CH 2 Cl 2 /MeOH (10:1) to N-[4-[3-(benzyloxy)piperidine-1- yl]phenyl]-5-(2-chloroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-amine (60 mg, 65.14% ) was obtained as an off-white solid. MS m/z: 528/530 [M+H] + .

단계 8: 1-(4-{[5-(2-클로로에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노}페닐)피페리딘-3-올(실시예 48의 화합물)의 합성Step 8: 1-(4-{[5-(2-chloroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-2-yl] Synthesis of amino} phenyl) piperidin-3-ol (compound of Example 48)

단계 7에서 수득된 화합물 (60 mg, 0.11 mmol, 1.00당량) 및 BBr3 (1M)을 DCM (3.00 mL) 중에 질소 대기하에 25℃에서 1시간 동안 교반하였다. 반응을 0℃에서 MeOH (1 mL)로 ??칭시켰다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Shield RP18 OBD 컬럼, 30×150 mm, 5 um; 이동상, 물 (10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN (32% Phase B, 7분에 62%까지); 검출기, UV 254/220 nm. 수집된 분획을 동결건조하여 1-(4-{[5-(2-클로로에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노}페닐)피페리딘-3-올 (실시예 48의 화합물; 9.9 mg, 19.06%)을 백색 고체로 수득하였다. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 8.96 (s, 1H), 7.87 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 2H), 5.55-5.53 (m, 1H), 5.39-5.37 (m, 1H), 4.77-4.76 (m, 1H), 4.03-3.87 (m, 4H), 3.72-3.44 (m, 4H), 3.36-3.33 (m, 1H), 3.11-2.95 (m, 2H), 2.42-2.35 (m, 2H), 1.90-1.84 (m, 1H), 1.77-1.70 (m, 1H), 1.55-1.51 (m, 1H), 1.22-1.19 (m 1H); MS m/z: 438/440 [M+H]+.The compound obtained in step 7 (60 mg, 0.11 mmol, 1.00 equiv) and BBr3 (1M) were stirred in DCM (3.00 mL) under a nitrogen atmosphere at 25° C. for 1 hour. The reaction was quenched with MeOH (1 mL) at 0 °C. The crude product was purified by Prep-HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 30×150 mm, 5 um; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (32% Phase B, up to 62% in 7 min); Detector, UV 254/220 nm. The collected fractions were lyophilized to obtain 1-(4-{[5-(2-chloroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine- Obtained 2-yl]amino}phenyl)piperidin-3-ol (compound of Example 48; 9.9 mg, 19.06%) as a white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.96 (s, 1H), 7.87 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 2H), 5.55-5.53 (m, 1H), 5.39-5.37 (m, 1H), 4.77-4.76 (m, 1H), 4.03-3.87 (m, 4H), 3.72-3.44 (m, 4H) ( m, 1H), 1.22-1.19 (m 1H); MS m/z: 438/440 [M+H] + .

실시예 49: 1-(4-{[5-(2-브로모에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 49: 1-(4-{[5-(2-bromoethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine-2- yl]amino}phenyl)piperidin-3-ol

Figure pct00121
Figure pct00121

실시예 48의 화합물 (40 mg, 0.091 mmol, 1.00당량)을 아세톤 (5.00 mL) 중에 교반 혼합하고, NaBr (94 mg, 0.91 mmol, 10.00당량)을 첨가하였다. 생성된 혼합물을 질소 대기하에 80℃에서 48시간 동안 교반하였다. 혼합물을 실온으로 냉각하고, 반응을 물 (20 mL)로 ??칭시켰다. 생성된 혼합물을 EtOAc (3×20 mL)로 추출하고, 유기층을 모아서 무수 Na2SO4 상에서 건조시켰다. 여과 후 여액을 감압 농축시키고, 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Shield RP18 OBD 컬럼, 19×150 mm, 5 um; 이동상, 물 (10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN (44% Phase B, 10분에 48%까지); 검출기, UV 254/220 nm. 수집된 분획을 동결건조하여 1-(4-{[5-(2-브로모에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노}페닐)피페리딘-3-올 (실시예 49의 화합물; 5.0 mg, 10.55%)을 황백색 고체로 수득하였다. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 8.87 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 5.55-5.37 (m, 2H), 4.77 (d, J = 4.8 Hz, 1H), 4.28-3.82 (m, 4H), 3.61-3.45 (m, 4H), 3.36-3.32 (m, 1H), 3.25-3.08 (m, 2H), 2.49-2.35 (m, 2H), 1.88-1.84 (m, 1H), 1.78-1.72 (m, 1H), 1.60-1.50 (m, 1H), 1.28-1.15 (m, 1H); MS m/z: 482/484 [M+H]+.The compound of Example 48 (40 mg, 0.091 mmol, 1.00 equiv) was stirred mixed in acetone (5.00 mL) and NaBr (94 mg, 0.91 mmol, 10.00 equiv) was added. The resulting mixture was stirred at 80° C. for 48 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and the reaction was quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 19×150 mm, 5 um; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (44% Phase B, up to 48% in 10 min); Detector, UV 254/220 nm. The collected fractions were lyophilized to obtain 1-(4-{[5-(2-bromoethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine Obtained -2-yl]amino}phenyl)piperidin-3-ol (compound of Example 49; 5.0 mg, 10.55%) as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.87 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 5.55-5.37 (m, 2H), 4.77 (d, J = 4.8 Hz, 1H), 4.28-3.82 (m, 4H), 3.61-3.45 (m, 4H), 3.36-3.32 (m , 1H), 3.25-3.08 (m, 2H), 2.49-2.35 (m, 2H), 1.88-1.84 (m, 1H), 1.78-1.72 (m, 1H), 1.60-1.50 (m, 1H), 1.28 -1.15 (m, 1H); MS m/z: 482/484 [M+H] + .

실시예 50: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(2-요오도에틸)피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 50: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(2-iodoethyl)pyrimidine-2- yl}amino)phenyl]piperidin-3-ol

Figure pct00122
Figure pct00122

아세톤 (5.00 mL) 중에 실시예 48의 화합물 (50 mg, 0.11 mmol, 1.00당량)을 교반 혼합하고, NaI (171 mg, 1.14 mmol, 10.00당량)을 첨가하였다. 생성된 혼합물을 질소 대기하에 100℃에서 48시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 생성된 혼합물을 진공 하에 농축시키고, 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, XBridge Prep OBD C18 컬럼, 30×150 mm, 5 um; 이동상, 물 (10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN (33% Phase B, 7분에 63%까지); 검출기, UV 254/220 nm. 수집된 분획을 동결건조하여 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(2-요오도에틸)피리미딘-2-일}아미노)페닐]피페리딘-3-올 (실시예 50의 화합물; 14.0 mg, 23.07%)을 황백색 고체로 수득하였다. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 8.72 (s, 1H), 7.66 (s, 1H), 7.55 (d, J = 9.0 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 5.20-4.70 (m, 3H), 3.91-3.80 (m, 1H), 3.77-3.40 (m, 7H), 3.92-2.86 (m, 1H), 2.60-2.55 (m, 1H), 2.40-2.33 (m, 1H), 1.89-1.84 (m, 1H), 1.76-1.70 (m, 1H), 4.59-1.51 (m, 1H), 1.26-1.15 (m, 1H); MS m/z: 530 [M+H]+.Stir-mix the compound of Example 48 (50 mg, 0.11 mmol, 1.00 equiv) in acetone (5.00 mL) and add NaI (171 mg, 1.14 mmol, 10.00 equiv). The resulting mixture was stirred at 100° C. for 48 hours under a nitrogen atmosphere, and the mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo and the crude product was purified by Prep-HPLC with the following conditions: column, XBridge Prep OBD C18 column, 30×150 mm, 5 um; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (33% Phase B, up to 63% in 7 min); Detector, UV 254/220 nm. The collected fractions were lyophilized to obtain 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(2-iodoethyl)pyrimidine Obtained -2-yl}amino)phenyl]piperidin-3-ol (compound of Example 50; 14.0 mg, 23.07%) as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.72 (s, 1H), 7.66 (s, 1H), 7.55 (d, J = 9.0 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 5.20-4.70 (m, 3H), 3.91-3.80 (m, 1H), 3.77-3.40 (m, 7H), 3.92-2.86 (m, 1H), 2.60-2.55 (m, 1H) , 2.40-2.33 (m, 1H), 1.89-1.84 (m, 1H), 1.76-1.70 (m, 1H), 4.59-1.51 (m, 1H), 1.26-1.15 (m, 1H); MS m/z: 530 [M+H] + .

실시예 51: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(3,3,3-트리플루오로프로필)피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 51: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(3,3,3-trifluoropropyl) pyrimidin-2-yl}amino)phenyl]piperidin-3-ol

Figure pct00123
Figure pct00123

실시예 51의 화합물을 하기 반응식 5에 따라서 합성하였다.The compound of Example 51 was synthesized according to Scheme 5 below.

[반응식 5][Scheme 5]

Figure pct00124
Figure pct00124

단계 1: 2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(3,3,3-트리플루오로프로필)피리미딘의 합성Step 1: Synthesis of 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(3,3,3-trifluoropropyl)pyrimidine

제조예 5의 화합물 (100 mg, 0.40 mmol, 1.00당량) 및 (3S,4S)-3,4-디플루오로피롤리딘 염산염 (100 mg, 0.40 mmol, 1.00당량)을 ACN (3 mL) 중에 교반 혼합하고, DIEA (158 mg, 1.22 mmol, 3.00당량)를 적가하였다. 혼합물을 질소 대기하에 60℃에서 3시간 동안 교반하고, 생성된 혼합물을 감압 농축시켰다. 잔사를 PE/EtOAc (2:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(3,3,3-트리플루오로프로필)피리미딘 (100 mg, 74%)을 백색 고체로 수득하였다. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.09 (s, 1H), 5.53 (s, 1H), 5.41 (s, 1H), 4.12-4.02 (m, 1H), 3.99-3.94 (m, 2H), 3.01-2.89 (m, 2H), 2.67-2.58 (m, 2H); MS m/z: 312/314 [M+H]+.The compound of Preparation 5 (100 mg, 0.40 mmol, 1.00 equiv) and (3S,4S)-3,4-difluoropyrrolidine hydrochloride (100 mg, 0.40 mmol, 1.00 equiv) were mixed in ACN (3 mL). Mix by stirring and add DIEA (158 mg, 1.22 mmol, 3.00 equiv) dropwise. The mixture was stirred at 60° C. for 3 hours under a nitrogen atmosphere, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5 Obtained -(3,3,3-trifluoropropyl)pyrimidine (100 mg, 74%) as a white solid. 1 H-NMR (DMSO-d 6 , 400 MHz) δ (ppm): 8.09 (s, 1H), 5.53 (s, 1H), 5.41 (s, 1H), 4.12-4.02 (m, 1H), 3.99- 3.94 (m, 2H), 3.01-2.89 (m, 2H), 2.67-2.58 (m, 2H); MS m/z: 312/314 [M+H] + .

단계 2: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(3,3,3-트리플루오로프로필)피리미딘-2-일}아미노)페닐]피페리딘-3-올(실시예 51의 화합물)의 합성Step 2: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(3,3,3-trifluoropropyl)pyridine Synthesis of midin-2-yl}amino)phenyl]piperidin-3-ol (compound of Example 51)

단계 1에서 수득된 화합물 (80 mg, 0.25 mmol, 1.00당량) 및 1-(4-아미노페닐)피페리딘-3-올 (73 mg, 0.38 mmol, 1.50당량)을 n-BuOH (2 mL) 중에 교반 혼합하고, HCl (1 방울)을 첨가하였다. 생성된 혼합물을 질소 대기하에 80℃에서 2시간 동안 교반하였다. 혼합물을 실온으로 냉각하고 감압 농축시켰다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: (컬럼: Xselect CSH OBD 컬럼, 30×150 mm, 5 um, n; 이동상 A: 물 (10 mmol/L NH4HCO3 + 0.1% NH3·H2O), 이동상 B: ACN 및 THF; 유속: 60 mL/min; 구배: 9분에 50% B ~ 80% B, 80% B; 파장: 254 nm; RT1(분): 7.23). 수집된 분획을 동결건조하여 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(3,3,3-트리플루오로프로필)피리미딘-2-일}아미노)페닐]피페리딘-3-올 (실시예 51의 화합물; 13.6 mg, 11%)을 백색 고체로 수득하였다. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.86 (s, 1H), 7.89 (s, 1H), 7.53(d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 5.53-5.52 (m, 1H), 5.41-5.39 (m, 1H), 4.77 (d, J = 4.8 Hz, 1H), 4.05-3.84 (m, 4H), 3.68-3.55 (m, 1H), 3.49-3.42 (m, 1H), 3.39-3.32 (m, 1H), 2.86-2.78 (m, 2H), 2.56-2.50 (m, 1H), 2.49-2.39 (m, 3H), 1.89-1.85 (m, 1H), 1.75-1.71 (m, 1H), 1.54-1.51 (m, 1H), 1.23-1.19 (m, 1H); MS m/z: 472 [M+H]+.The compound obtained in step 1 (80 mg, 0.25 mmol, 1.00 equiv) and 1-(4-aminophenyl)piperidin-3-ol (73 mg, 0.38 mmol, 1.50 equiv) were added to n-BuOH (2 mL). Mix by stirring and add HCl (1 drop). The resulting mixture was stirred at 80° C. for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH OBD column, 30×150 mm, 5 um, n; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 H 2 O), mobile phase B: ACN and THF; flow rate: 60 mL/min; gradient: 50% B to 80% B, 80% B in 9 min; wavelength: 254 nm; RT1 (min): 7.23). The collected fractions were lyophilized to obtain 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(3,3,3-trifluoro Obtained ropropyl)pyrimidin-2-yl}amino)phenyl]piperidin-3-ol (compound of example 51; 13.6 mg, 11%) as a white solid. 1 H-NMR (DMSO-d 6 , 400 MHz) δ (ppm): 8.86 (s, 1H), 7.89 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 5.53-5.52 (m, 1H), 5.41-5.39 (m, 1H), 4.77 (d, J = 4.8 Hz, 1H), 4.05-3.84 (m, 4H), 3.68-3.55 (m , 1H), 3.49-3.42 (m, 1H), 3.39-3.32 (m, 1H), 2.86-2.78 (m, 2H), 2.56-2.50 (m, 1H), 2.49-2.39 (m, 3H), 1.89 -1.85 (m, 1H), 1.75-1.71 (m, 1H), 1.54-1.51 (m, 1H), 1.23-1.19 (m, 1H); MS m/z: 472 [M+H] + .

실시예 52: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-6-(트리플루오로메틸)피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 52: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidin-2-yl }amino)phenyl]piperidin-3-ol

Figure pct00125
Figure pct00125

실시예 51의 단계 1에서 제조예 5의 화합물 대신에 2,4-디클로로-6-(트리플루오로메틸)피리미딘을 사용한 것을 제외하고, 실시예 51과 동일한 방법으로 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-6-(트리플루오로메틸)피리미딘-2-일}아미노)페닐]피페리딘-3-올 (실시예 52의 화합물; 14.2　mg, 15.2%)을 황백색 고체로 수득하였다. 1H NMR (DMSO-d6, 400 MHz) δ (ppm): δ 9.41 (s, 1H), 7.58 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 6.39 (s, 1H), 5.57-5.46 (m, 2H), 4.78 (d, J = 4.8 Hz, 1H), 4.19-3.72 (m, 4H), 3.66-3.46 (m, 2H), 3.39-3.36 (m, 1H), 2.56-2.53 (m, 1H), 2.44-2.38 (m, 1H), 1.95-1.81 (m, 1H), 1.76-1.71 (m, 1H), 1.54-1.51 (m, 1H), 1.26-1.21 (m, 1H); MS m/z: 444 [M+H]+.In step 1 of Example 51, 1-[4-({ 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]piperidin-3- Ole (compound of Example 52; 14.2 mg, 15.2%) was obtained as an off-white solid. 1 H NMR (DMSO-d 6 , 400 MHz) δ (ppm): δ 9.41 (s, 1H), 7.58 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 6.39 (s, 1H), 5.57-5.46 (m, 2H), 4.78 (d, J = 4.8 Hz, 1H), 4.19-3.72 (m, 4H), 3.66-3.46 (m, 2H), 3.39-3.36 (m) , 1H), 2.56-2.53 (m, 1H), 2.44-2.38 (m, 1H), 1.95-1.81 (m, 1H), 1.76-1.71 (m, 1H), 1.54-1.51 (m, 1H), 1.26 -1.21 (m, 1H); MS m/z: 444 [M+H] + .

실시예 53: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 53: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl }amino)phenyl]piperidin-3-ol

Figure pct00126
Figure pct00126

실시예 51의 단계 1에서 제조예 5의 화합물 대신에 2,4-디클로로-5-(트리플루오로메틸)피리미딘을 사용한 것을 제외하고, 실시예 51과 동일한 방법으로 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일)-5-(트리플루오로메틸)피리미딘-2-일}아미노)페닐]피페리딘-3-올 (실시예 53의 화합물; 7.9 mg, 10.18%)을 황백색 고체로 수득하였다. 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 9.54 (s, 1H), 8.35 (s, 1H), 7.52 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 5.59-5.58 (m, 1H), 5.42-5.40 (s, 1H), 4.79-4.78 (m, 1H), 4.06-3.82 (m, 4H), 3.62-3.49 (m, 2H), 3.41-3.37 (m, 1H), 2.61-2.53 (m, 1H), 2.49-2.39 (m, 1H), 1.90-1.85 (m, 1H), 1.77-1.72 (m, 1H), 1.60-1.50 (m, 1H), 1.28-1.18 (m, 1H); MS m/z: 444 [M+H]+.In step 1 of Example 51, 1-[4-({ 4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]piperidin-3- Ole (compound of Example 53; 7.9 mg, 10.18%) was obtained as an off-white solid. 1 H NMR (DMSO-d 6 , 300 MHz) δ (ppm): 9.54 (s, 1H), 8.35 (s, 1H), 7.52 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 5.59-5.58 (m, 1H), 5.42-5.40 (s, 1H), 4.79-4.78 (m, 1H), 4.06-3.82 (m, 4H), 3.62-3.49 (m, 2H), 3.41-3.37 (m, 1H), 2.61-2.53 (m, 1H), 2.49-2.39 (m, 1H), 1.90-1.85 (m, 1H), 1.77-1.72 (m, 1H), 1.60-1.50 (m , 1H), 1.28-1.18 (m, 1H); MS m/z: 444 [M+H] + .

실시예 54: 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(2,2,2-트리플루오로에틸)피리미딘-2-일}아미노)페닐]피페리딘-3-올Example 54: 1-[4-({4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-(2,2,2-trifluoroethyl) pyrimidin-2-yl}amino)phenyl]piperidin-3-ol

Figure pct00127
Figure pct00127

실시예 51의 단계 1에서 제조예 5의 화합물 대신에 제조예 6의 화합물을 사용한 것을 제외하고, 실시예 51과 동일한 방법으로 1-[4-({4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-(2,2,2-트리플루오로에틸)피리미딘-2-일}아미노)페닐]피페리딘-3-올 (실시예 54의 화합물; 7.3 mg, 9.54%)을 황백색 고체로 수득하였다. 1H-NMR (400 MHz, DMSO-d6) δ 10.08 (br s, 1H), 8.02 (s, 1H), 7.66-7.57 (m, 2H), 7.25-7.12 (m, 2H), 5.58 (s, 1H), 5.45 (s, 1H), 4.45-4.00 (m, 4H), 3.96-3.71 (m, 3H), 3.59-3.48 (m, 2H), 2.93-2.67 (m, 2H), 1.92-1.87 (m, 2H), 1.70-1.60 (m, 1H), 1.45-1.35 (m, 1H); MS m/z: 458 [M+H]+.1-[4-({4-[(3S,4S)-3, 4-difluoropyrrolidin-1-yl]-5-(2,2,2-trifluoroethyl)pyrimidin-2-yl}amino)phenyl]piperidin-3-ol (Example 54 of the compound; 7.3 mg, 9.54%) as an off-white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.08 (br s, 1H), 8.02 (s, 1H), 7.66-7.57 (m, 2H), 7.25-7.12 (m, 2H), 5.58 (s , 1H), 5.45 (s, 1H), 4.45-4.00 (m, 4H), 3.96-3.71 (m, 3H), 3.59-3.48 (m, 2H), 2.93-2.67 (m, 2H), 1.92-1.87 (m, 2H), 1.70-1.60 (m, 1H), 1.45-1.35 (m, 1H); MS m/z: 458 [M+H] + .

실시예 55: 1-(4-{[5-(2,2-디플루오로에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노}페닐)피페리딘-3-올Example 55: 1-(4-{[5-(2,2-difluoroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine -2-yl]amino}phenyl)piperidin-3-ol

Figure pct00128
Figure pct00128

실시예 55의 화합물을 하기 반응식 6에 따라서 합성하였다.The compound of Example 55 was synthesized according to Scheme 6 below.

[반응식 6][Scheme 6]

Figure pct00129
Figure pct00129

단계 1: 2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-요오도피리미딘의 합성Step 1: Synthesis of 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-iodopyrimidine

ACN (5.00 mL) 중에 2,4-디클로로-5-요오도피리미딘 (300 mg, 1.09 mmol, 1.00당량) 및 (3S,4S)-3,4-디플루오로피롤리딘 염산염 (188 mg, 1.31 mmol, 1.20당량)을 교반 혼합하고, DIEA (423 mg, 3.27 mmol, 3.00당량)를 첨가하였다. 생성된 혼합물을 질소 대기하에 80℃에서 3시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 생성된 혼합물을 감압 농축시키고, 잔사를 PE/EtOAc (1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-요오도피리미딘 (300 mg, 75.57%)를 황백색 고체로 수득하였다. MS m/z: 346/348 [M+H]+.2,4-dichloro-5-iodopyrimidine (300 mg, 1.09 mmol, 1.00 equiv) and (3S,4S)-3,4-difluoropyrrolidine hydrochloride (188 mg, 1.31 mmol, 1.20 equiv) were stirred and mixed, and DIEA (423 mg, 3.27 mmol, 3.00 equiv) was added. The resulting mixture was stirred at 80° C. for 3 hours under a nitrogen atmosphere, and the mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to give 2-chloro-4-[(3S,4S)-3,4-difluoropyrroly Obtained din-1-yl]-5-iodopyrimidine (300 mg, 75.57%) as an off-white solid. MS m/z: 346/348 [M+H] + .

단계 2: 2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-[(Z)-2-에톡시에테닐]피리미딘의 합성Step 2: Synthesis of 2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5-[(Z)-2-ethoxyethenyl]pyrimidine

상기 단계 1에서 수득된 화합물 (300 mg, 0.86 mmol, 1.00당량) 및 트리부틸[(Z)-2-에톡시에테닐]스탄난 (470 mg, 1.30 mmol, 1.50당량)을 DMF (5.00 mL) 중에 교반 혼합하고, Pd(PPh3)2Cl2 (121.89 mg, 0.17 mmol, 0.20당량)를 첨가하였다. 생성된 혼합물을 질소 대기하에 80℃에서 3시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 반응을 물 (30 mL)로 ??칭시키고, 생성된 혼합물을 EtOAc (3×30 mL)로 추출하였다. 유기층을 모아서 염수 (3×30 mL)로 세척하여, 무수 Na2SO4 상에서 건조시켰다. 여과 후 여액을 감압 농축시키고, 잔사를 PE/EtOAc (1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]-5-[(Z)-2-에톡시에테닐]피리미딘 (120 mg, 42.94%)를 황백색 고체로 수득하였다. MS m/z: 290/292 [M+H]+.The compound obtained in step 1 (300 mg, 0.86 mmol, 1.00 equiv) and tributyl[(Z)-2-ethoxyethenyl]stannane (470 mg, 1.30 mmol, 1.50 equiv) were mixed in DMF (5.00 mL). Mixing was stirred, and Pd(PPh 3 ) 2 Cl 2 (121.89 mg, 0.17 mmol, 0.20 eq.) was added. The resulting mixture was stirred at 80° C. for 3 hours under a nitrogen atmosphere, and the mixture was cooled to room temperature. The reaction was quenched with water (30 mL) and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3×30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was eluted with PE/EtOAc (1:1) and purified by silica gel column chromatography to obtain 2-chloro-4-[(3S,4S)-3,4-difluoropyrroly Obtained din-1-yl]-5-[(Z)-2-ethoxyethenyl]pyrimidine (120 mg, 42.94%) as an off-white solid. MS m/z: 290/292 [M+H] + .

단계 3: 2-[2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-5-일]아세트알데히드의 합성Step 3: Synthesis of 2-[2-chloro-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidin-5-yl]acetaldehyde

상기 단계 2에서 수득된 화합물 (120 mg)을 THF (3.00 mL) 중에 교반 혼합하고, H2O (3.00 mL) 중의 HCl (4M)을 적가하였다. 생성된 혼합물을 질소 대기하에 60℃에서 7시간 동안 교반하고, 혼합물을 실온으로 냉각시켰다. 생성된 혼합물을 감압 농축시키고, 잔사를 PE/EtOAc (1:10)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2-[2-클로로-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-5-일]아세트알데히드(50 mg, 41.52%)를 황백색 고체로 수득하였다. MS m/z: 262/264 [M+H]+.The compound obtained in step 2 above (120 mg) was stirred and mixed in THF (3.00 mL), and HCl (4M) in H 2 O (3.00 mL) was added dropwise. The resulting mixture was stirred at 60° C. for 7 hours under a nitrogen atmosphere, and the mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:10) to give 2-[2-chloro-4-[(3S,4S)-3,4-difluoro Obtained ropyrrolidin-1-yl]pyrimidin-5-yl]acetaldehyde (50 mg, 41.52%) as an off-white solid. MS m/z: 262/264 [M+H] + .

단계 4: 2-클로로-5-(2,2-디플루오로에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘의 합성Step 4: Synthesis of 2-chloro-5-(2,2-difluoroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine

상기 단계 3에서 수득된 화합물 (50 mg, 0.19 mmol, 1.00당량)을 DCM (5.00 mL) 중에 교반 혼합하고, 디에틸아미노 황 트리플루오라이드(Diethylaminosulfur trifluoride; DAST) (61 mg, 0.38 mmol, 2.00당량)를 적가하였다. 생성된 혼합물을 질소 대기하에 25℃에서 2시간 동안 교반하였다. 생성된 혼합물을 진공 하에 농축시키고, 잔사를 PE/EtOAc (1:1)로 용출시켜서 실리카겔 컬럼 크로마토그래피로 정제하여 2-클로로-5-(2,2-디플루오로에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘 (35 mg, 58.12%)을 연황색 고체로 수득하였다. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 8.09 (s, 1H), 6.49-6.09 (m, 1H), 5.56-5.54 (m, 1H), 5.39-5.37 (m, 1H), 4.07-4.05 (m, 2H), 4.00-3.93 (m, 2H), 3.47-3.36 (m, 2H); MS m/z: 284/286 [M+H]+.The compound obtained in step 3 (50 mg, 0.19 mmol, 1.00 eq.) was mixed with stirring in DCM (5.00 mL), and diethylaminosulfur trifluoride (DAST) (61 mg, 0.38 mmol, 2.00 eq.) ) was added dropwise. The resulting mixture was stirred at 25° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give 2-chloro-5-(2,2-difluoroethyl)-4-[( Obtained 3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine (35 mg, 58.12%) as a pale yellow solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 8.09 (s, 1H), 6.49-6.09 (m, 1H), 5.56-5.54 (m, 1H), 5.39-5.37 (m, 1H) ), 4.07-4.05 (m, 2H), 4.00-3.93 (m, 2H), 3.47-3.36 (m, 2H); MS m/z: 284/286 [M+H] + .

단계 5: 1-(4-[[5-(2,2-디플루오로에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노]페닐)피페리딘-3-올의 합성Step 5: 1-(4-[[5-(2,2-difluoroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]pyrimidine- Synthesis of 2-yl]amino]phenyl)piperidin-3-ol

상기 단계 4에서 수득된 화합물 (35.00 mg, 0.123 mmol, 1.00당량)을 n-BuOH (2 mL) 중에 교반 혼합하고, 1-(4-아미노페닐)피페리딘-3-올 (35 mg, 0.18 mmol, 1.50당량) 및 농염산 (1 방울)을 첨가하였다. 생성된 혼합물을 질소 대기하에 80℃에서 2시간 동안 교반하였다. 혼합물을 실온으로 냉각시키고, 생성된 혼합물을 MeOH (1 mL)로 희석하였다. 조 생성물을 하기 조건으로 Prep-HPLC로 정제하였다: 컬럼, YMC-Actus Triart C18 ExRS, 30×250 mm, 5 um; 이동상, 물 (10 mmol/L NH4HCO3 + 0.1% NH3·H2O) 및 ACN (40% Phase B, 7분에 60%까지); 검출기, UV 254/220 nm. 수집된 분획을 동결건조하여 1-(4-{[5-(2,2-디플루오로에틸)-4-[(3S,4S)-3,4-디플루오로피롤리딘-1-일]피리미딘-2-일]아미노}페닐)피페리딘-3-올 (실시예 55의 화합물; 10.3 mg, 18.58%)을 황백색 고체로 수득하였다. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.90 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 6.35-5.97 (m, 1H), 5.54-5.53 (m, 1H), 5.37-5.35 (m, 1H), 4.77-4.76 (m, 1H), 4.09-3.90 (m, 4H), 3.63-3.36 (m, 2H), 3.27-3.14 (m, 2H), 2.42-2.26 (m, 3H), 1.95-1.82 (m, 1H), 1.80-70 (m, 1H), 1.65-1.48 (m, 1H), 1.25-1.18 (m, 1H); MS m/z: 440 [M+H]+.The compound obtained in step 4 above (35.00 mg, 0.123 mmol, 1.00 equiv) was stirred and mixed in n-BuOH (2 mL), and 1-(4-aminophenyl)piperidin-3-ol (35 mg, 0.18 mmol, 1.50 eq) and concentrated hydrochloric acid (1 drop) were added. The resulting mixture was stirred at 80° C. for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and the resulting mixture was diluted with MeOH (1 mL). The crude product was purified by Prep-HPLC with the following conditions: column, YMC-Actus Triart C18 ExRS, 30×250 mm, 5 um; mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (40% Phase B, up to 60% in 7 min); Detector, UV 254/220 nm. The collected fractions were lyophilized to obtain 1-(4-{[5-(2,2-difluoroethyl)-4-[(3S,4S)-3,4-difluoropyrrolidin-1-yl Obtained ]pyrimidin-2-yl]amino}phenyl)piperidin-3-ol (compound of Example 55; 10.3 mg, 18.58%) as an off-white solid. 1 H-NMR (DMSO-d 6 , 300 MHz) δ (ppm): 9.90 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 6.35-5.97 (m, 1H), 5.54-5.53 (m, 1H), 5.37-5.35 (m, 1H), 4.77-4.76 (m, 1H), 4.09-3.90 (m, 4H) ( m, 1H), 1.25-1.18 (m, 1H); MS m/z: 440 [M+H] + .

실험예 1. LRRK2 효소 억제 효과의 확인Experimental Example 1. Confirmation of LRRK2 enzyme inhibitory effect

실시예에서 제조된 화합물의 LRRK2 효소 저해 활성이 있는지 여부를 확인하였다. LRRK2 효소 저해 활성은 Nat Biotechnol. 2011 Oct 30;29(11):1039-45에 기재된 방법에 따라 수행하였다.It was confirmed whether the compounds prepared in Examples had LRRK2 enzyme inhibitory activity. LRRK2 enzyme inhibitory activity was evaluated by Nat Biotechnol. 2011 Oct 30;29(11):1039-45.

화합물은 100% DMSO에 용해시켜 스톡 용액을 준비하였다. 50% 저해 농도(half maximal inhibitory concentration: IC50)을 결정하기 위해, 화합물을 최고 농도 10 μM로 하고, 3배씩 희석하여 10가지 농도로 준비하였다.Compounds were dissolved in 100% DMSO to prepare stock solutions. To determine the half maximal inhibitory concentration (IC 50 ), compounds were prepared at the highest concentration of 10 μM and diluted 3-fold to 10 concentrations.

LRRK2 G2019S 효소(Invitrogen, PR8764C)와 기질로서 LRRKtide(SignalChem, L10-58)를 준비하였다. 30 nM LRRK2(G2019S), 20 μM LRRKtide, 10 μM ATP, 및 반응 완충액(20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01%(v/v) Brij35, 0.02 mg/mL BSA, 0.1 mM Na3VO4, 2 mM DTT, 및 1%(w/v) DMSO)을 준비하였다.LRRK2 G2019S enzyme (Invitrogen, PR8764C) and LRRKtide (SignalChem, L10-58) were prepared as a substrate. 30 nM LRRK2(G2019S), 20 μM LRRKtide, 10 μM ATP, and reaction buffer (20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.01% (v/v) Brij35, 0.02 mg/mL BSA , 0.1 mM Na 3 VO 4 , 2 mM DTT, and 1% (w/v) DMSO) were prepared.

신선한 반응 완충액에 20 μM LRRKtide을 가하고, 30 nM LRRK2(G2019S) 효소를 가한 후 부드럽게 혼합하였다. 준비된 화합물(100% DMSO 중)을 Acoustic technology (Echo550; 나노 수준)를 사용하여 LRRK2(G2019S) 혼합물에 가하였다. 반응 혼합물에 33P-ATP를 가하여 반응을 개시한 후, 실온에서 2시간 동안 인큐베이션하였다. P81 필터-결합 방법으로 LRRK2(G2019S)에 대한 IC50를 산출하고, 그 결과를 하기 표 1의 기준으로 평가하여 표 2에 나타내었다.20 μM LRRKtide was added to the fresh reaction buffer, 30 nM LRRK2 (G2019S) enzyme was added and mixed gently. The prepared compound (in 100% DMSO) was added to the LRRK2 (G2019S) mixture using Acoustic technology (Echo550; nanoscale). After the reaction was initiated by adding 33 P-ATP to the reaction mixture, it was incubated at room temperature for 2 hours. The IC 50 for LRRK2 (G2019S) was calculated by the P81 filter-binding method, and the results were evaluated based on the criteria in Table 1 below and are shown in Table 2.

IC50(LRRK2 G2019S)IC 50 (LRRK2 G2019S) 기준(IC50)Standard (IC 50 ) <50nM<50 nM 50-500nM50-500 nM >500nM>500nM 표시값display value ++++++ ++++ ++

LRRK2 길항 활성
(IC50, nM)LRRK2 antagonistic activity
(IC 50 , nM) LRRK2 길항 활성
(IC50, nM)LRRK2 antagonistic activity
(IC 50 , nM) 실시예 1Example 1 ++++++ 실시예 28Example 28 ++++++ 실시예 2Example 2 ++++ 실시예 29Example 29 ++++ 실시예 3Example 3 ++++ 실시예 30Example 30 ++++ 실시예 4Example 4 ++ 실시예 31Example 31 ++++++ 실시예 5Example 5 ++ 실시예 32Example 32 ++++++ 실시예 6Example 6 ++++++ 실시예 33Example 33 ++++++ 실시예 7Example 7 ++++++ 실시예 34Example 34 ++ 실시예 8Example 8 ++++ 실시예 35Example 35 ++ 실시예 9Example 9 ++++++ 실시예 36Example 36 ++++ 실시예 10Example 10 ++++ 실시예 37Example 37 ++++++ 실시예 11Example 11 ++ 실시예 38Example 38 ++++++ 실시예 12Example 12 ++++++ 실시예 39Example 39 ++++++ 실시예 13Example 13 ++++++ 실시예 40Example 40 ++++ 실시예 14Example 14 ++++++ 실시예 41Example 41 ++++++ 실시예 15Example 15 ++++++ 실시예 42Example 42 ++++++ 실시예 16Example 16 ++++++ 실시예 43Example 43 ++++ 실시예 17Example 17 ++++++ 실시예 44Example 44 ++++++ 실시예 18Example 18 ++++++ 실시예 45Example 45 ++++++ 실시예 19Example 19 ++++++ 실시예 46Example 46 ++++++ 실시예 20Example 20 ++++++ 실시예 47Example 47 ++++++ 실시예 21Example 21 ++++++ 실시예 48Example 48 ++ 실시예 22Example 22 ++++++ 실시예 49Example 49 ++ 실시예 23Example 23 ++++++ 실시예 50Example 50 ++ 실시예 24Example 24 ++++++ 실시예 51Example 51 ++ 실시예 24(R)Example 24 (R) ++++++ 실시예 52Example 52 ++ 실시예 24(S)Example 24(S) ++++++ 실시예 53Example 53 ++++++ 실시예 25Example 25 ++++++ 실시예 54Example 54 ++ 실시예 26Example 26 ++++++ 실시예 55Example 55 ++ 실시예 27Example 27 ++++++

표 2의 데이터로부터 본원 화합물이 우수한 LRRK2 길항 활성을 나타냄을 확인할 수 있었다.From the data in Table 2, it was confirmed that the present compound exhibits excellent LRRK2 antagonistic activity.

Claims (18)

하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염:
[화학식 1]
Figure pct00130

상기 화학식 1에서,
R1은 할로겐으로 치환된 C1-6 알킬이고;
R2는 할로겐; OH; CN; 아미노; 니트로; C1-6 알킬; C1-6 알콕시; 포르밀; C1-6 알킬카보닐; 모노- 또는 디-C1-6 알킬아미노; 포르밀아미노; C1-6 알킬카보닐아미노; 모노- 또는 디-C1-6 알킬아미노카보닐; 포르밀옥시; 및 C1-6 알킬카보닐옥시로 이루어진 군으로부터 선택되고, 상기 C1-6 알킬, C1-6 알콕시, C1-6 알킬카보닐, 모노- 또는 디-C1-6 알킬아미노, C1-6 알킬카보닐아미노, 모노- 또는 디-C1-6 알킬아미노카보닐, 및 C1-6 알킬카보닐옥시는 할로겐, OH, CN, 아미노 또는 니트로로 임의로 치환될 수 있고;
고리 A 및 B는 각각 독립적으로, 페닐 고리 또는 피리미딘 고리에 결합된 N과 함께, 임의로 N, O 및 S에서 선택된 1개의 추가 헤테로원자를 포함하는 3원 내지 10원 헤테로모노사이클릴이고;
상기 고리 A 및 B는 각각 독립적으로, 할로겐; OH; CN; 옥소; 아미노; 니트로; C1-6 알킬; C1-6 알콕시; 모노- 또는 디-C1-6 알킬아미노; 및 N, O 및 S로부터 선택된 1~3개의 헤테로원자를 함유하는 3원 내지 8원 헤테로모노사이클릴로 이루어진 군으로부터 선택된 1~3개의 치환기로 임의로 치환될 수 있고, 상기 C1-6 알킬, C1-6 알콕시, 모노- 또는 디-C1-6 알킬아미노는 할로겐, OH, CN, 옥소, 아미노 또는 니트로로 임의로 치환될 수 있고, 상기 3원 내지 8원 헤테로모노사이클릴은 할로겐, OH, CN, 옥소, 아미노, 니트로, C1-6 알킬, C1-6 알콕시, 모노- 또는 디-C1-6 알킬아미노로 임의로 치환될 수 있고;
n은 0 내지 3의 정수이다.A compound represented by Formula 1 below, a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
[Formula 1]
Figure pct00130

In Formula 1,
R 1 is C 1-6 alkyl substituted with halogen;
R 2 is halogen; OH; CN; amino; nitro; C 1-6 alkyl; C 1-6 alkoxy; formyl; C 1-6 alkylcarbonyl; mono- or di-C 1-6 alkylamino; formylamino; C 1-6 alkylcarbonylamino; mono- or di-C 1-6 alkylaminocarbonyl; formyloxy; And C 1-6 It is selected from the group consisting of alkylcarbonyloxy, said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl, mono- or di-C 1-6 Alkylamino, C 1-6 alkylcarbonylamino, mono- or di-C 1-6 alkylaminocarbonyl, and C 1-6 alkylcarbonyloxy may be optionally substituted with halogen, OH, CN, amino or nitro;
rings A and B are each independently a 3- to 10-membered heteromonocyclyl containing 1 additional heteroatom optionally selected from N, O and S, together with N bonded to the phenyl ring or pyrimidine ring;
The rings A and B are each independently selected from halogen; OH; CN; iodine; amino; nitro; C 1-6 alkyl; C 1-6 alkoxy; mono- or di-C 1-6 alkylamino; and a 3- to 8-membered heteromonocyclyl containing 1 to 3 heteroatoms selected from N, O and S, optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, mono- or di-C 1-6 alkylamino can be optionally substituted with halogen, OH, CN, oxo, amino or nitro, wherein the 3-8 membered heteromonocyclyl is halogen, OH, optionally substituted with CN, oxo, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, mono- or di-C 1-6 alkylamino;
n is an integer from 0 to 3; 제1항에 있어서,
R1은 F, Cl, Br 및 I로 이루어진 군으로부터 각각 독립적으로 선택된 1~3개의 할로겐 원자로 치환된 C1-3 알킬인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염.According to claim 1,
R 1 is C 1-3 alkyl substituted with 1 to 3 halogen atoms each independently selected from the group consisting of F, Cl, Br and I, a compound, a stereoisomer, solvate or pharmaceutically acceptable salt thereof. 제1항에 있어서,
R2는 할로겐; OH; CN; 아미노; 니트로; C1-6 알킬; C1-6 알콕시; C1-6 알킬카보닐; 및 모노- 또는 디-C1-6 알킬아미노로 이루어진 군으로부터 선택되고, 상기 C1-6 알킬, C1-6 알콕시, C1-6 알킬카보닐, 및 모노- 또는 디-C1-6 알킬아미노는 할로겐, OH, CN, 아미노 또는 니트로로 임의로 치환될 수 있고, n은 0 내지 2의 정수인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염.According to claim 1,
R 2 is halogen; OH; CN; amino; nitro; C 1-6 alkyl; C 1-6 alkoxy; C 1-6 alkylcarbonyl; and mono- or di-C 1-6 alkylamino, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, and mono- or di-C 1-6 wherein alkylamino may be optionally substituted with halogen, OH, CN, amino or nitro, where n is an integer from 0 to 2, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof. 제1항에 있어서,
R2는 할로겐, CN, 할로겐으로 임의로 치환된 C1-6 알킬, 할로겐으로 임의로 치환된 C1-6 알콕시, 할로겐으로 임의로 치환된 C1-6 알킬카보닐, 또는 할로겐으로 임의로 치환된 모노- 또는 디-C1-6 알킬아미노이고, n은 0 내지 2의 정수인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염.According to claim 1,
R 2 is halogen, CN, C 1-6 alkyl optionally substituted with halogen, C 1-6 alkoxy optionally substituted with halogen, C 1-6 alkylcarbonyl optionally substituted with halogen, or mono-6 alkyl optionally substituted with halogen. or di-C 1-6 alkylamino, wherein n is an integer from 0 to 2, or a stereoisomer, solvate or pharmaceutically acceptable salt thereof. 제1항에 있어서,
고리 A 및 B는 각각 독립적으로, 페닐 고리 또는 피리미딘 고리에 결합된 N과 함께, 임의로 N, O 및 S에서 선택된 1개의 추가 헤테로 원자를 포함하는 4원 내지 9원 헤테로모노사이클릴인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염.According to claim 1,
Rings A and B are each independently a 4- to 9-membered heteromonocyclyl, together with N bonded to the phenyl ring or pyrimidine ring, optionally containing 1 additional heteroatom selected from N, O and S; , a stereoisomer, solvate or pharmaceutically acceptable salt thereof. 제5항에 있어서,
고리 A 및 B는 각각 독립적으로, 아제티딘일, 피롤리딘일, 피페리딘일, 피페라진일, 모르폴린일, 티오모르폴린일, 아제판일, 디아제판일, 옥사제판일 및 티아제판일로 이루어진 군으로부터 선택되는 것인, 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염.According to claim 5,
Rings A and B are each independently selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl and thiazepanyl A compound selected from, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof. 제6항에 있어서,
고리 A 및 B는 각각 독립적으로, 아제티딘일, 피롤리딘일, 피페리딘일, 모르폴린일, 아제판일 또는 옥사제판일인, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염. According to claim 6,
A compound, a stereoisomer, solvate or pharmaceutically acceptable salt thereof, wherein rings A and B are each independently azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl or oxazepanyl. 제1항에 있어서,
고리 A 및 B는 각각 독립적으로, 할로겐; OH; CN; 옥소; 아미노; C1-6 알킬; C1-6 알콕시; 피롤리딘일; 피페리딘일; 피페라진일; 모르폴린일; 및 티오모르폴린일로 이루어진 군으로부터 선택된 1~3개의 치환기로 임의로 치환되는, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염.According to claim 1,
Rings A and B are each independently halogen; OH; CN; iodine; amino; C 1-6 alkyl; C 1-6 alkoxy; pyrrolidinyl; piperidinyl; piperazinyl; morpholinyl; and thiomorpholinyl; and thiomorpholinyl. 제8항에 있어서,
고리 A 및 B는 각각 독립적으로, 할로겐; OH; CN; 옥소; 아미노; C1-6 알킬; 및 모르폴린일로 이루어진 군으로부터 선택된 1~2개의 치환기로 임의로 치환되는, 화합물, 이의 입체이성질체, 용매화물 또는 약학적으로 허용가능한 염.According to claim 8,
Rings A and B are each independently halogen; OH; CN; iodine; amino; C 1-6 alkyl; and morpholinyl; and morpholinyl. 제1항에 있어서,
상기 화학식 1의 화합물은 하기 화합물로 이루어진 군으로부터 선택되는 것인 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염:
Figure pct00131
Figure pct00132
Figure pct00133

Figure pct00134
Figure pct00135
Figure pct00136

Figure pct00137
Figure pct00138
Figure pct00139

Figure pct00140
Figure pct00141
Figure pct00142

Figure pct00143
Figure pct00144
Figure pct00145

Figure pct00146
Figure pct00147
Figure pct00148

Figure pct00149
Figure pct00150
Figure pct00151

Figure pct00152
Figure pct00153
Figure pct00154

Figure pct00155
Figure pct00156
Figure pct00157

Figure pct00158
Figure pct00159
Figure pct00160

Figure pct00161
Figure pct00162
Figure pct00163

Figure pct00164
Figure pct00165
Figure pct00166

Figure pct00167
Figure pct00168
Figure pct00169

Figure pct00170
Figure pct00171
Figure pct00172

Figure pct00173
Figure pct00174
Figure pct00175

Figure pct00176
Figure pct00177
Figure pct00178

Figure pct00179
Figure pct00180
Figure pct00181

Figure pct00182
Figure pct00183
Figure pct00184

Figure pct00185
Figure pct00186
및
Figure pct00187
.According to claim 1,
The compound of Formula 1 is a compound selected from the group consisting of the following compounds, stereoisomers, solvates, or pharmaceutically acceptable salts thereof:
Figure pct00131
Figure pct00132
Figure pct00133

Figure pct00134
Figure pct00135
Figure pct00136

Figure pct00137
Figure pct00138
Figure pct00139

Figure pct00140
Figure pct00141
Figure pct00142

Figure pct00143
Figure pct00144
Figure pct00145

Figure pct00146
Figure pct00147
Figure pct00148

Figure pct00149
Figure pct00150
Figure pct00151

Figure pct00152
Figure pct00153
Figure pct00154

Figure pct00155
Figure pct00156
Figure pct00157

Figure pct00158
Figure pct00159
Figure pct00160

Figure pct00161
Figure pct00162
Figure pct00163

Figure pct00164
Figure pct00165
Figure pct00166

Figure pct00167
Figure pct00168
Figure pct00169

Figure pct00170
Figure pct00171
Figure pct00172

Figure pct00173
Figure pct00174
Figure pct00175

Figure pct00176
Figure pct00177
Figure pct00178

Figure pct00179
Figure pct00180
Figure pct00181

Figure pct00182
Figure pct00183
Figure pct00184

Figure pct00185
Figure pct00186
and
Figure pct00187
. 제1항의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 포함하는 LRRK2(Leucine-rich repeat kinase 2)에 의해 매개되거나 이와 관련된 질병 또는 질환을 예방 또는 치료하기 위한 약학적 조성물.A pharmaceutical composition for preventing or treating a disease or disorder mediated by or related to LRRK2 (Leucine-rich repeat kinase 2), comprising the compound of claim 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof. 제11항에 있어서,
상기 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환은 퇴행성 뇌질환인 것인 약학적 조성물.According to claim 11,
A pharmaceutical composition wherein the disease or disorder mediated by or related to LRRK2 is a degenerative brain disease. 제12항에 있어서,
상기 퇴행성 뇌질환은 파킨슨병(Parkinson's disease), 알츠하이머병(Alzheimer's disease), 헌팅턴병(Huntington's disease), 경도인지장애(mild cognitive impairment), 아밀로이드증(amyloidosis), 다계통위측증(Multiple system atrophy), 다발성경화증(multiple sclerosis), 타우병증(tauopathies), 픽병(Pick's disease), 노인성 치매, 근위축성 측삭 경화증(amyotrophic lateral sclerosis), 척수소뇌성 운동실조증(Spinocerebellar Atrophy), 뚜렛 증후군(Tourette's Syndrome), 프리드리히 보행실조(Friedrich's Ataxia), 마차도-조셉 병(Machado-Joseph's disease), 루이 소체 치매(Lewy Body Dementia), 근육긴장이상(Dystonia), 진행성 핵상 마비(Progressive Supranuclear Palsy) 및 전두측두엽 치매(Frontotemporal Dementia)로 이루어진 군에서 선택된 것인 약학적 조성물.According to claim 12,
The degenerative brain diseases include Parkinson's disease, Alzheimer's disease, Huntington's disease, mild cognitive impairment, amyloidosis, multiple system atrophy, multiple Multiple sclerosis, tauopathies, Pick's disease, senile dementia, amyotrophic lateral sclerosis, Spinocerebellar Atrophy, Tourette's Syndrome, Friedrich Gait Friedrich's Ataxia, Machado-Joseph's disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy and Frontotemporal Dementia A pharmaceutical composition selected from the group consisting of. 제12항에 있어서,
상기 퇴행성 뇌질환은 파킨슨병인 것인 약학적 조성물.According to claim 12,
The degenerative brain disease is a pharmaceutical composition that is Parkinson's disease. 제11항에 있어서,
상기 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환은 운동이상증, 중추신경계 장애, 암, 류마티스 관절염, 강직성 척추염, 크론병, 염증성 장질환 및 결핵으로 이루어진 군으로부터 선택되는 것인, 약학적 조성물.According to claim 11,
The disease or disease mediated by or related to LRRK2 is selected from the group consisting of dyskinesia, central nervous system disorder, cancer, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, inflammatory bowel disease and tuberculosis, a pharmaceutical composition. 제1항의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 개체에게 투여하는 단계를 포함하는 LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환을 예방 또는 치료하는 방법.A method for preventing or treating a disease or condition mediated by or related to LRRK2, comprising administering the compound of claim 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof to a subject. LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환 또는 질환의 예방 또는 치료에 사용하기 위한 제1항에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도.Use of the compound according to claim 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease or disorder or condition mediated by or related to LRRK2. LRRK2에 의해 매개되거나 이와 관련된 질병 또는 질환 또는 질환을 예방 또는 치료하기 위한 의약을 제조하기 위한 제1항에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도.Use of a compound according to claim 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing or treating a disease or disorder or condition mediated by or related to LRRK2.
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